Histone demethylase inhibitors

ABSTRACT

The present disclosure relates generally to compositions and methods for treating cancer and neoplastic disease. Provided herein are substituted pyridine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application 62/017,201, filed Jun. 25, 2014, which is incorporated herein by reference in its entirety.

BACKGROUND

A need exists in the art for an effective treatment of cancer and neoplastic disease.

BRIEF SUMMARY OF THE INVENTION

Provided herein are substituted pyridine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like. The substituted pyridine derivative compounds described herein are based upon a disubstituted pyridine ring bearing at the 4-position a carboxylic acid, a carboxylic acid ester, or a carboxylic acid bioisostere thereof, and at the 3-position a substituted amino group.

One embodiment provides a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of Formula (I):

wherein,

-   -   X is O or CH₂;     -   each R⁵, R⁶, R⁷ and R⁸ is independently chosen from hydrogen,         optionally substituted heterocyclyl, optionally substituted         heterocyclyloxy, optionally substituted heterocyclylalkyl,         optionally substituted heterocyclylalkoxy, optionally         substituted C₆-C₁₀ aryl-SO₂—, optionally substituted         heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or         optionally substituted alkyl, and R² is chosen from optionally         substituted alkyl, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted cycloalkyl, optionally substituted         cycloalkylalkyl, optionally substituted aryl-CO—, optionally         substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—;         with the provision that at least one of R⁵, R⁶, R⁷ or R⁸ is not         hydrogen.

One embodiment provides a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of Formula (II):

wherein,

-   -   X is O or CH₂;     -   R⁶ is chosen from optionally substituted heterocyclyl,         optionally substituted heterocyclyloxy, optionally substituted         heterocyclylalkyl, optionally substituted heterocyclylalkoxy,         optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted         heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or         optionally substituted alkyl, and R² is chosen from optionally         substituted alkyl, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted cycloalkyl, optionally substituted         cycloalkylalkyl, optionally substituted aryl-CO—, optionally         substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—; and     -   each R⁵, R⁷ and R⁸ is independently chosen from hydrogen,         halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl,         optionally substituted C₁-C₆ alkoxy, optionally substituted         C₃-C₇ carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy,         optionally substituted C₄-C₁₂ carbocyclylalkyl, optionally         substituted C₄-C₁₂ carbocyclylalkoxy, optionally substituted         C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl, optionally         substituted C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,         optionally substituted C₆-C₁₀ aryl-S—, optionally substituted         C₇-C₁₄ aralkoxy, optionally substituted heteroaryl, and         optionally substituted heteroaryloxy, optionally substituted         heterocyclyl, optionally substituted heterocyclyloxy,         substituted heterocyclylalkyl, optionally substituted         heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—,         optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹         is hydrogen or optionally substituted alkyl, and R² is chosen         from optionally substituted alkyl, optionally substituted aryl,         optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted cycloalkyl, optionally         substituted cycloalkylalkyl, optionally substituted aryl-CO—,         optionally substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—;         with the provision that at least one of R⁵, R⁷ and R⁸ is         hydrogen.

One embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt thereof, having the structure of Formula (IIa):

wherein,

-   -   X is O or CH₂;     -   R⁶ is chosen from optionally substituted heterocyclyl,         optionally substituted heterocyclyloxy, optionally substituted         heterocyclylalkyl, optionally substituted heterocyclylalkoxy,         optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted         heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or         optionally substituted alkyl, and R² is chosen from optionally         substituted alkyl, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted cycloalkyl, optionally substituted         cycloalkylalkyl, optionally substituted aryl-CO—, optionally         substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—; and     -   each R⁵, R⁷ and R⁸ is independently chosen from hydrogen,         halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl,         optionally substituted C₁-C₆ alkoxy, optionally substituted         C₃-C₇ carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy,         optionally substituted C₄-C₁₂ carbocyclylalkyl, optionally         substituted C₄-C₁₂ carbocyclylalkoxy, optionally substituted         C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl, optionally         substituted C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,         optionally substituted C₆-C₁₀ aryl-S—, optionally substituted         C₇-C₁₄ aralkoxy, optionally substituted heteroaryl, and         optionally substituted heteroaryloxy, optionally substituted         heterocyclyl, optionally substituted heterocyclyloxy,         substituted heterocyclylalkyl, optionally substituted         heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—,         optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹         is hydrogen or optionally substituted alkyl, and R² is chosen         from optionally substituted alkyl, optionally substituted aryl,         optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted cycloalkyl, optionally         substituted cycloalkylalkyl, optionally substituted aryl-CO—,         optionally substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—;

with the provision that at least one of R⁵, R⁷ and R⁸ is hydrogen.

One embodiment provides a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of Formula (III):

wherein,

-   -   X is O or CH₂;     -   at least one of R⁵, R⁶, R⁷ and R⁸ is chosen from optionally         substituted heterocyclyl, optionally substituted         heterocyclyloxy, optionally substituted heterocyclylalkyl,         optionally substituted heterocyclylalkoxy, optionally         substituted C₆-C₁₀ aryl-SO₂—, optionally substituted         heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or         optionally substituted alkyl, and R² is chosen from optionally         substituted alkyl, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted cycloalkyl, optionally substituted         cycloalkylalkyl, optionally substituted aryl-CO—, optionally         substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—; and     -   the remaining R⁵, R⁶, R⁷ and R⁸ groups are independently chosen         from hydrogen, halogen, —OH, —CN, optionally substituted C₁-C₆         alkyl, optionally substituted C₁-C₆ alkoxy, optionally         substituted C₃-C₇ carbocyclyl, optionally substituted C₃-C₇         carbocyclyloxy, optionally substituted C₄-C₁₂ carbocyclylalkyl,         optionally substituted C₄-C₁₂ carbocyclylalkoxy, optionally         substituted C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl,         optionally substituted C₆-C₁₀ aryl, optionally substituted         C₆-C₁₀ aryloxy, optionally substituted C₆-C₁₀ aryl-S—,         optionally substituted C₇-C₁₄ aralkoxy, optionally substituted         heteroaryl, and optionally substituted heteroaryloxy, optionally         substituted heterocyclyl, optionally substituted         heterocyclyloxy, substituted heterocyclylalkyl, optionally         substituted heterocyclylalkoxy, optionally substituted C₆-C₁₀         aryl-SO₂—, optionally substituted heteroaryl-S—, or —N(R¹)(R²),         wherein R¹ is hydrogen or optionally substituted alkyl, and R²         is chosen from optionally substituted alkyl, optionally         substituted aryl, optionally substituted heteroaryl, optionally         substituted heterocyclyl, optionally substituted cycloalkyl,         optionally substituted cycloalkylalkyl, optionally substituted         aryl-CO—, optionally substituted heteroaryl-CO—, optionally         substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.

One embodiment provides a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of Formula (V):

wherein,

-   -   X is O or CH₂;     -   R⁶ is chosen from optionally substituted heterocyclyl,         optionally substituted heterocyclyloxy, optionally substituted         heterocyclylalkyl, optionally substituted heterocyclylalkoxy,         optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted         heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or         optionally substituted alkyl, and R² is chosen from optionally         substituted alkyl, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted cycloalkyl, optionally substituted         cycloalkylalkyl, optionally substituted aryl-CO—, optionally         substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—; and     -   each R⁵, R⁷ and R⁸ is independently chosen from hydrogen,         halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl,         optionally substituted C₁-C₆ alkoxy, optionally substituted         C₃-C₇ carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy,         optionally substituted C₄-C₁₂ carbocyclylalkyl, optionally         substituted C₄-C₁₂ carbocyclylalkoxy, optionally substituted         C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl, optionally         substituted C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,         optionally substituted C₆-C₁₀ aryl-S—, optionally substituted         C₇-C₁₄ aralkoxy, optionally substituted heteroaryl, and         optionally substituted heteroaryloxy, optionally substituted         heterocyclyl, optionally substituted heterocyclyloxy,         substituted heterocyclylalkyl, optionally substituted         heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—,         optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹         is hydrogen or optionally substituted alkyl, and R² is chosen         from optionally substituted alkyl, optionally substituted aryl,         optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted cycloalkyl, optionally         substituted cycloalkylalkyl, optionally substituted aryl-CO—,         optionally substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—;

with the provision that at least one of R⁵, R⁷ and R⁸ is hydrogen.

One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a substituted pyridine derivative compound as described herein, or a stereoisomer or pharmaceutically acceptable salt thereof.

One embodiment provides a method of inhibiting a histone demethylase enzyme comprising contacting the histone demethylase enzyme with a substituted pyridine derivative compound as described herein, or a stereoisomer thereof.

One embodiment provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a composition comprising a substituted pyridine derivative compound as described herein, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may “consist of” or “consist essentially of” the described features.

DEFINITIONS

As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅ alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅ alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In other embodiments, an alkyl comprises two to ten carbon atoms (e.g., C₂-C₁₀ alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₅ alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C₁-C₄ alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C₁ alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C₃-C₅ alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C (O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^(b) is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^(c) is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d) is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e) is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of the formula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl may be saturated, (i.e., containing single C—C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds.) A fully saturated carbocyclyl radical is also referred to as “cycloalkyl.” Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “carbocyclyl” is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C (O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^(b) is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^(c) is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclyl where R^(c) is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—R^(c)-carbocyclyl where R^(c) is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo substituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C (O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^(b) is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^(c) is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula —R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

“Heteroaryl” refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C (O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^(b) is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^(c) is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl, where R^(c) is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom of the formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

As used herein, “carboxylic acid bioisostere” refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,

and the like.

The compounds, or their pharmaceutically acceptable salts, in some instances, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers (e.g., cis or trans). Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. It is contemplated that the disclosure provided herein encompasses the various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecular structures are nonsuperimposable mirror images of one another.

A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein may, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

“Optional” or “optionally” means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

“Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the substituted pyridine derivative compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S. M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997), which is hereby incorporated by reference in its entirety). Acid addition salts of basic compounds may be prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

“Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

“Prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.

Substituted Pyridine Derivative Compounds

Substituted pyridine derivative compounds are described herein that inhibit a histone demethylase enzyme. These compounds, and compositions comprising these compounds, are useful for the treatment of cancer and neoplastic disease. The compounds described herein, in some embodiments, are useful for treating prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.

One embodiment provides a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of Formula (I):

wherein,

-   -   X is O or CH₂;     -   each R⁵, R⁶, R⁷ and R⁸ is independently chosen from hydrogen,         optionally substituted heterocyclyl, optionally substituted         heterocyclyloxy, optionally substituted heterocyclylalkyl,         optionally substituted heterocyclylalkoxy, optionally         substituted C₆-C₁₀ aryl-SO₂—, optionally substituted         heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or         optionally substituted alkyl, and R² is chosen from optionally         substituted alkyl, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted cycloalkyl, optionally substituted         cycloalkylalkyl, optionally substituted aryl-CO—, optionally         substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—;

with the provision that at least one of R⁵, R⁶, R⁷ or R⁸ is not hydrogen.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (I), wherein X is O. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (I), wherein X is CH₂.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (I), wherein R⁵ is hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (I), wherein R⁷ is hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (I), wherein R⁸ is hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (I), wherein R⁷ and R⁸ are hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (I), wherein R⁶ is not hydrogen.

One embodiment provides a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of Formula (II):

wherein,

-   -   X is O or CH₂;     -   R⁶ is chosen from optionally substituted heterocyclyl,         optionally substituted heterocyclyloxy, optionally substituted         heterocyclylalkyl, optionally substituted heterocyclylalkoxy,         optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted         heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or         optionally substituted alkyl, and R² is chosen from optionally         substituted alkyl, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted cycloalkyl, optionally substituted         cycloalkylalkyl, optionally substituted aryl-CO—, optionally         substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—; and     -   each R⁵, R⁷ and R⁸ is independently chosen from hydrogen,         halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl,         optionally substituted C₁-C₆ alkoxy, optionally substituted         C₃-C₇ carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy,         optionally substituted C₄-C₁₂ carbocyclylalkyl, optionally         substituted C₄-C₁₂ carbocyclylalkoxy, optionally substituted         C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl, optionally         substituted C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,         optionally substituted C₆-C₁₀ aryl-S—, optionally substituted         C₇-C₁₄ aralkoxy, optionally substituted heteroaryl, and         optionally substituted heteroaryloxy, optionally substituted         heterocyclyl, optionally substituted heterocyclyloxy,         substituted heterocyclylalkyl, optionally substituted         heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—,         optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹         is hydrogen or optionally substituted alkyl, and R² is chosen         from optionally substituted alkyl, optionally substituted aryl,         optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted cycloalkyl, optionally         substituted cycloalkylalkyl, optionally substituted aryl-CO—,         optionally substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—;

with the provision that at least one of R⁵, R⁷ and R⁸ is hydrogen.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein X is O. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein X is CH₂. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein each R⁵, R⁷ and R⁸ is independently chosen from hydrogen, halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆ alkoxy.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁵ is hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁷ is hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁸ is hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁷ and R⁸ are hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is not hydrogen.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is optionally substituted heterocyclyl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is optionally substituted heterocyclyloxy. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is optionally substituted heterocyclylalkyl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is optionally substituted heterocyclylalkoxy. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is optionally substituted C₆-C₁₀ aryl-SO₂—, or optionally substituted heteroaryl-S—.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²), wherein R¹ is hydrogen and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted alkyl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted aryl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted heteroaryl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted heterocyclyl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted cycloalkyl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted cycloalkylalkyl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted aryl-CO—. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted heteroaryl-CO—. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted cycloalkyl-CO—. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted alkyl-CO—.

One embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt thereof, having the structure of Formula (IIa):

wherein,

-   -   X is O or CH₂;     -   R⁶ is chosen from optionally substituted heterocyclyl,         optionally substituted heterocyclyloxy, optionally substituted         heterocyclylalkyl, optionally substituted heterocyclylalkoxy,         optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted         heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or         optionally substituted alkyl, and R² is chosen from optionally         substituted alkyl, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted cycloalkyl, optionally substituted         cycloalkylalkyl, optionally substituted aryl-CO—, optionally         substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—; and     -   each R⁵, R⁷ and R⁸ is independently chosen from hydrogen,         halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl,         optionally substituted C₁-C₆ alkoxy, optionally substituted         C₃-C₇ carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy,         optionally substituted C₄-C₁₂ carbocyclylalkyl, optionally         substituted C₄-C₁₂ carbocyclylalkoxy, optionally substituted         C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl, optionally         substituted C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,         optionally substituted C₆-C₁₀ aryl-S—, optionally substituted         C₇-C₁₄ aralkoxy, optionally substituted heteroaryl, and         optionally substituted heteroaryloxy, optionally substituted         heterocyclyl, optionally substituted heterocyclyloxy,         substituted heterocyclylalkyl, optionally substituted         heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—,         optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹         is hydrogen or optionally substituted alkyl, and R² is chosen         from optionally substituted alkyl, optionally substituted aryl,         optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted cycloalkyl, optionally         substituted cycloalkylalkyl, optionally substituted aryl-CO—,         optionally substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—;

with the provision that at least one of R⁵, R⁷ and R⁸ is hydrogen.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein X is O. Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein X is CH₂.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁵ is hydrogen. Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁷ is hydrogen. Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁸ is hydrogen. Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ are hydrogen. Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein X is O; and R⁵, R⁷ and R⁸ are hydrogen.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁶ is optionally substituted heterocyclyl, or optionally substituted heterocyclyloxy.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁶ is optionally substituted C₆-C₁₀ aryl-SO₂—, or optionally substituted heteroaryl-S—.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁶ is —N(R¹)(R²), wherein R¹ is hydrogen; and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted aryl.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted heteroaryl.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is an optionally substituted C1-C3 alkyl; and R² is optionally substituted aryl. Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is an optionally substituted C1-C3 alkyl; and R² is optionally substituted aryl.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is a CH₃ group; and R² is optionally substituted aryl. Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is a CH₃ group; and R² is optionally substituted aryl.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted aryl substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, halogen, cyano, hydroxy, amino, optionally substituted C1-C5 alkoxy, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkoxy, or optionally substituted cycloalkoxy. Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted aryl substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, halogen, cyano, hydroxy, amino, optionally substituted C1-C5 alkoxy, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkoxy, or optionally substituted cycloalkoxy.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted aryl substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, halogen, optionally substituted C1-C5 alkoxy, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkoxy, or optionally substituted cycloalkoxy. Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted aryl substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, halogen, optionally substituted C1-C5 alkoxy, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkoxy, or optionally substituted cycloalkoxy.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted aryl substituted with at least one substituent selected from optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkoxy, or optionally substituted cycloalkoxy. Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted aryl substituted with at least one substituent selected from optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkoxy, or optionally substituted cycloalkoxy.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted aryl substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, halogen, or optionally substituted C1-C5 alkoxy. Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted aryl substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, halogen, or optionally substituted C1-C5 alkoxy.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted aryl substituted with at least one optionally substituted C1-C5 alkyl. Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted aryl substituted with at least one optionally substituted C1-C5 alkyl.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is a CH₃ group; and R² is optionally substituted aryl substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, halogen, or optionally substituted C1-C5 alkoxy.

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, having the structure:

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, having the structure:

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, having the structure:

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, selected from:

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, selected from:

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, selected from:

Another embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, selected from:

One embodiment provides a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of Formula (III):

wherein,

-   -   X is O or CH₂;     -   at least one of R⁵, R⁶, R⁷ and R⁸ is chosen from optionally         substituted heterocyclyl, optionally substituted         heterocyclyloxy, optionally substituted heterocyclylalkyl,         optionally substituted heterocyclylalkoxy, optionally         substituted C₆-C₁₀ aryl-SO₂—, optionally substituted         heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or         optionally substituted alkyl, and R² is chosen from optionally         substituted alkyl, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted cycloalkyl, optionally substituted         cycloalkylalkyl, optionally substituted aryl-CO—, optionally         substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—; and     -   the remaining R⁵, R⁶, R⁷ and R⁸ groups are independently chosen         from hydrogen, halogen, —OH, —CN, optionally substituted C₁-C₆         alkyl, optionally substituted C₁-C₆ alkoxy, optionally         substituted C₃-C₇ carbocyclyl, optionally substituted C₃-C₇         carbocyclyloxy, optionally substituted C₄-C₁₂ carbocyclylalkyl,         optionally substituted C₄-C₁₂ carbocyclylalkoxy, optionally         substituted C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl,         optionally substituted C₆-C₁₀ aryl, optionally substituted         C₆-C₁₀ aryloxy, optionally substituted C₆-C₁₀ aryl-S—,         optionally substituted C₇-C₁₄ aralkoxy, optionally substituted         heteroaryl, and optionally substituted heteroaryloxy, optionally         substituted heterocyclyl, optionally substituted         heterocyclyloxy, substituted heterocyclylalkyl, optionally         substituted heterocyclylalkoxy, optionally substituted C₆-C₁₀         aryl-SO₂—, optionally substituted heteroaryl-S—, or —N(R¹)(R²),         wherein R¹ is hydrogen or optionally substituted alkyl, and R²         is chosen from optionally substituted alkyl, optionally         substituted aryl, optionally substituted heteroaryl, optionally         substituted heterocyclyl, optionally substituted cycloalkyl,         optionally substituted cycloalkylalkyl, optionally substituted         aryl-CO—, optionally substituted heteroaryl-CO—, optionally         substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein X is O. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein X is CH₂. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein each R⁵, R⁷ and R⁸ is independently chosen from hydrogen, halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆ alkoxy.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁵ is hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁷ is hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁸ is hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁷ and R⁸ are hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is not hydrogen.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is optionally substituted heterocyclyl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is optionally substituted heterocyclyloxy. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is optionally substituted heterocyclylalkyl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is optionally substituted heterocyclylalkoxy. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is optionally substituted C₆-C₁₀ aryl-SO₂—, or optionally substituted heteroaryl-S—.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), wherein R¹ is hydrogen and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted alkyl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted aryl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted heteroaryl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted heterocyclyl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted cycloalkyl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted cycloalkylalkyl. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted aryl-CO—. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted heteroaryl-CO—. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted cycloalkyl-CO—. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), and R² is optionally substituted alkyl-CO—.

One embodiment provides a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of Formula (IV):

wherein,

-   -   X is O or CH₂;     -   R⁶ is an optionally substituted aryl, optionally substituted         heteroaryl, or —N(R¹)(R²), wherein R¹ is hydrogen or optionally         substituted alkyl, and R² is chosen from optionally substituted         aryl or optionally substituted heteroaryl; and     -   each R⁷ and R⁸ is independently chosen from hydrogen, halogen,         —OH, —CN, optionally substituted C₁-C₆ alkyl, or optionally         substituted C₁-C₆ alkoxy.

One embodiment provides a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of Formula (V):

wherein,

-   -   X is O or CH₂;     -   R⁶ is chosen from optionally substituted heterocyclyl,         optionally substituted heterocyclyloxy, optionally substituted         heterocyclylalkyl, optionally substituted heterocyclylalkoxy,         optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted         heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or         optionally substituted alkyl, and R² is chosen from optionally         substituted alkyl, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl,         optionally substituted cycloalkyl, optionally substituted         cycloalkylalkyl, optionally substituted aryl-CO—, optionally         substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—; and     -   each R⁵, R⁷ and R⁸ is independently chosen from hydrogen,         halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl,         optionally substituted C₁-C₆ alkoxy, optionally substituted         C₃-C₇ carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy,         optionally substituted C₄-C₁₂ carbocyclylalkyl, optionally         substituted C₄-C₁₂ carbocyclylalkoxy, optionally substituted         C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl, optionally         substituted C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,         optionally substituted C₆-C₁₀ aryl-S—, optionally substituted         C₇-C₁₄ aralkoxy, optionally substituted heteroaryl, and         optionally substituted heteroaryloxy, optionally substituted         heterocyclyl, optionally substituted heterocyclyloxy,         substituted heterocyclylalkyl, optionally substituted         heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—,         optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹         is hydrogen or optionally substituted alkyl, and R² is chosen         from optionally substituted alkyl, optionally substituted aryl,         optionally substituted heteroaryl, optionally substituted         heterocyclyl, optionally substituted cycloalkyl, optionally         substituted cycloalkylalkyl, optionally substituted aryl-CO—,         optionally substituted heteroaryl-CO—, optionally substituted         cycloalkyl-CO—, or optionally substituted alkyl-CO—;

with the provision that at least one of R⁵, R⁷ and R⁸ is hydrogen.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein X is O. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein X is CH₂.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵ is hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁷ is hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁸ is hydrogen. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷ and R⁸ are hydrogen.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁶ is optionally substituted heterocyclyl, or optionally substituted heterocyclyloxy.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁶ is optionally substituted C₆-C₁₀ aryl-SO₂—, or optionally substituted heteroaryl-S—.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁶ is —N(R¹)(R²), wherein R¹ is hydrogen; and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—. Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted aryl.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted heteroaryl.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted C1-C3 alkyl; and R² is optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is a CH₃ group; and R² is optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is an optionally substituted aryl substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, halogen, cyano, hydroxy, amino, optionally substituted C1-C5 alkoxy, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkoxy, or optionally substituted cycloalkoxy.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is an optionally substituted aryl substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, halogen, optionally substituted C1-C5 alkoxy, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkoxy, or optionally substituted cycloalkoxy.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is an optionally substituted aryl substituted with at least one substituent selected from optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkoxy, or optionally substituted cycloalkoxy.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is an optionally substituted aryl substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, halogen, or optionally substituted C1-C5 alkoxy.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is an optionally substituted aryl substituted with at least one optionally substituted C1-C5 alkyl.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is a CH₃ group; and R² is an optionally substituted aryl substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, halogen, or optionally substituted C1-C5 alkoxy.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein X is CH₂; R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is a CH₃ group; and R² is an optionally substituted aryl substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, halogen, or optionally substituted C1-C5 alkoxy.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is a CH₃ group; and R² is an optionally substituted aryl.

Another embodiment provides the compound, or a stereoisomer or pharmaceutically acceptable salt thereof, of Formula (V), wherein X is CH₂; R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is a CH₃ group; and R² is an optionally substituted aryl.

One embodiment provides a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, chosen from:

One embodiment provides a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, chosen from:

One embodiment provides a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, chosen from:

One embodiment provides a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, chosen from:

In some embodiments, the substituted pyridine derivative compound as described herein, or a stereoisomer or pharmaceutically acceptable salt thereof, has the structure provided in Table 1.

TABLE 1 Chemical Synthesis Example Structure Comments 1

3-({[(1S)-6-[methyl(phenyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 2

3-({[(1S)-6-[methyl(phenyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 3

3-({[6-(2-oxopyrrolidin-1-yl)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 4

3-({[6-(1,2,3,4-tetrahydroquinolin-1-yl)- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 5

3-({[6-(2,3-dihydro-1H-indol-1-yl)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 6

3-({[(1R)-6-[(2-fluorophenyl)(methyl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 7

3-({[(1R)-6-[(3-fluroophenyl)(methyl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 8

3-({[(1R)-6-[(4-fluorophenyl)(methyl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 9

3-({[(1R)-6-[(4-chlorophenyl)(methyl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 10

3-({[(1R)-6-[ethyl(phenyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 11

3-({[(1R)-6-[methyl(pyridin-2-yl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 12

3-({[(1R)-6-[methyl(pyridin-3-yl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 13

3-({[(1R)-6-[(6-methoxypyridin-3- yl)(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 14

3-{[(7-bromo-3,4-dihydro-2H-1-benzopyran-4- yl)methyl]amino}pyridine-4-carboxylic acid 15

3-({[7-(phenylamino)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 16

3-({[7-(1,2,3,4-tetrahydroquinolin-1-yl)-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 17

3-({[7-(2,3-dihydro-1H-indol-1-yl)-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 18

3-({[(4R)-7-[methyl(phenyl)amino]-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 19

3-({[(4R)-7-[(2-fluorophenyl)(methyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 20

3-({[(4R)-7-[(3-fluorophenyl)(methyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 21

3-({[(4R)-7-[(4-fluorophenyl)(methyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 22

3-({[(4R)-7-[methyl(4-methylphenyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 23

3-({[(4R)-7-[(4-chlorophenyl)(methyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 24

3-({[(4R)-7-[ethyl(phenyl)amino]-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 25

3-{[(2-phenyl-5,6,7,8-tetrahydroquinolin-5- yl)methyl]amino}pyridine-4-carboxylic acid 26

3-[({2-[methyl(phenyl)amino]-5,6,7,8- tetrahydroquinolin-5- yl}methyl)amino]pyridine-4-carboxylic acid 27

3-[({7-[4-(trifluoromethyl)phenyl]-3,4-dihydro- 2H-1-benzopyran-4-yl}methyl)amino]pyridine- 4-carboxylic acid 28

3-({[7-(furan-3-yl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 29

3-({[(4S)-7-(3-methylphenyl)-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 30

3-({[(4R)-7-(3-methylphenyl)-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 31

3-({[(4S)-7-(4-methylphenyl)-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 32

3-({[(4R)-7-(4-methylphenyl)-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 33

3-({[(4S)-7-(thiophen-3-yl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 34

3-({[(4R)-7-(thiophen-3-yl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 35

3-({[(4R)-7-cyclohexyl-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 36

3-({[(4S)-7-(2-methylthiophen-3-yl)-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 37

3-({[(4R)-7-(2-methylthiophen-3-yl)-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 38

3-({[7-(3-methylbut-1-yn-1-yl)-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 39

3-({[(4S)-7-(2-chlorophenyl)-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 40

3-({[(4R)-7-(2-chlorophenyl)-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 41

3-({[(4S)-7-(3-fluoro-2-methylphenyl)-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 42

3-({[(4R)-7-(3-fluoro-2-methylphenyl)-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 43

3-({[(4R)-7-(5-fluoro-2-methylphenyl)-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 44

3-({[(4R)-7-(2-chloro-3-fluorophenyl)-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 45

3-({[(4R)-7-(2-chloro-5-fluorophenyl)-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 46

3-({[(4R)-7-[2-(trifluoromethyl)phenyl]-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 47

3-({[(4S)-7-phenoxy-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 48

3-({[(4R)-7-phenoxy-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 49

3-({[7-(thiophen-2-ylsulfanyl)-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 50

3-({[(4S)-7-[(2-methylphenyl)sulfanyl]-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 51

3-({[(4R)-7-[(2-methylphenyl)sulfanyl]-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 52

3-({[(4S)-7-[(3-fluorophenyl)sulfanyl]-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 53

3-({[(4R)-7-[(3-fluorophenyl)sulfanyl]-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 54

3-({[(4S)-7-[(4-fluorophenyl)sulfanyl]-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 55

3-({[(4R)-7-[(4-fluorophenyl)sulfanyl]-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 56

3-[({6-[(6-methylpyridin-2-yl)oxy]-1,2,3,4- tetrahydronaphthalen-1- yl}methyl)amino]pyridine-4-carboxylic acid 57

3-({[(1S)-6-(2-methylphenoxy)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 58

3-({[(1R)-6-(2-methylphenoxy)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 59

3-{[(6-propoxy-1,2,3,4-tetrahydronaphthalen-1- yl)methyl]amino}pyridine-4-carboxylic acid 60

3-({[(1S)-6-(difluoromethoxy)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 61

3-({[(1R)-6-(difluoromethoxy)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 62

3-[({6-[2-(trifluoromethyl)phenoxy]-1,2,3,4- tetrahydronaphthalen-1- yl}methyl)amino]pyridine-4-carboxylic acid 63

3-({[6-(oxan-4-ylmethoxy)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 64

3-({[(1R)-6-(4-fluoro-2-methylphenoxy)- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 65

3-({[(1R)-6-(2,4-difluorophenoxy)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 66

3-({[(1R)-6-(2-fluoro-4-methylphenoxy)- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 67

3-({[(1R)-6-(2-chlorophenoxy)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 68

3-({[(1R)-6-[(3-methylphenyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 69

3-({[(1R)-6-[(3-methylphenyl)sulfanyl]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 70

3-({[(1S)-6-[(2-methylphenyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 71

3-({[(1R)-6-[(2-methylphenyl)sulfanyl]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 72

3-({[(1S)-6-[(2-fluoropehnyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 73

3-({[(1R)-6-[(2-fluoropehnyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 74

3-({[(1S)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 75

3-({[(1R)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 76

3-({[(1S)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 77

3-({[(1R)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 78

3-({[(1S)-6-[(4-methylphenyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 79

3-({[(1R)-6-[(4-methylphenyl)sulfamyl]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 80

3-({[6-(pyridin-2-ylsulfanyl)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 81

3-({[(1S)-6-(benzenesulfonyl)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 82

3-({[(1R)-6-(benzenesulfonyl)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 83

3-({[(1S)-6-(4-methylbenzenesulfonyl)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 84

3-({[(1R)-6-(4-methylbenzenesulfonyl)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 85

3-({[(1S)-6-(3-methylbenzenesulfonyl)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 86

3-({[(1R)-6-(3-methylbenzenesulfonyl)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 87

3-({[6-(3-fluorobenzenesulfonyl)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 88

3-({[6-(oxan-4-yl)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 89

3-({[6-(2-methylpyridin-4-yl)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid, hydrochloride 90

3-({[(1S)-6-ethyl-1,2,3,4-tetrahydronaphthalen- 1-yl]methyl}amino)pyridine-4-carboxylic acid 91

3-({[(1R)-6-ethyl-1,2,3,4-tetrahydronaphthalen- 1-yl]methyl}amino)pyridine-4-carboxylic acid 92

3-({2H,3H,6H,7H,8H,9H-naphtho[1,2-b]furan- 6-ylmethyl}amino)pyridine-4-carboxylic acid 93

3-{[(6,7-dimethyl-3,4-dihydro-2H-1- benzopyran-4-yl)methyl]amino}pyridine-4- carboxylic acid 94

3-{[(6-methoxy-7-methyl-1,2,3,4- tetrahydronaphthalen-1- yl)methyl]amino}pyridine-4-carboxylic acid 95

3-{[(6,8-dimethoxy-1,2,3,4- tetrahydronaphthalen-1- yl)methyl]amino}pyridine-4-carboxylic acid 96

3-({[(1S)-7-fluoro-6-methoxy-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 97

3-({[(1R)-7-fluoro-6-methoxy-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 98

3-({[(1S)-6-methoxy-5-methyl-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 99

3-({[(1R)-6-methoxy-5-methyl-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 100

3-({[(4S)-7-(2-methylphenyl)-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 101

3-({[(4R)-7-(2-methylphenyl)-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 102

3-({[(4R)-7-(5-fluoro-2-methoxyphenyl)-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 103

3-({[(1R)-6-[(4-cyanophenyl)(methyl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 104

3-({[(4R)-7-[(2,4- difluorophenyl)(methyl)amino]-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 105

3-({[(4R)-7-[methyl(3-methylphenyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 106

3-({[(1R)-6-(pyrrolidin-1-yl)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 107

3-({[(4R)-7-(2-chloro-5-methoxyphenyl)-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 108

3-({[(1R)-6-(3,4-dihydro-2H-1,4-benzoxazin-4- yl)-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 109

3-({[(4R)-7-[(3,5- difluorophenyl)(methyl)amino]-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 110

3-({[(4R)-7-[(3-chlorophenyl)(methyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 111

3-({[(4R)-7-[methyl(2-methylphenyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 112

3-({[(4R)-7-[(4-fluoro-3- methoxyphenyl)(methyl)amino]-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 113

3-({[(1R)-6-[methyl(oxan-4-yl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 114

3-({[(1R)-6-[(4-fluoro-3- methoxyphenyl)(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 115

3-({[(1R)-6-[(3-cyanophenyl)(methyl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 116

3-({[(4R)-7-(2-methoxyphenyl)-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 117

3-({[(4R)-7-[(3-cyanophenyl)(methyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 118

3-({[(4R)-7-(4-fluoro-2-methoxyphenyl)-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 119

3-({[(4R)-7-[(4-cyanophenyl)(methyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 120

3-({[(1R)-6- [(cyclopropylmethyl)(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 121

3-({[(1R)-6-[methyl(6-methoxypyridin-2- yl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 122

3-({[(1R)-6-[methyl(5-methylpyridin-2- yl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 123

3-({[(1R)-6-[methyl(6-methylpyridin-2- yl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 124

3-({[(4R)-7-(2-cyanophenyl)-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 125

3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-3- yl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 126

3-({[(4)R-7-[(4-ethynylphenyl)(methyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 127

3-({[(4R)-7-[(1,3-dihydro-2-benzofuran-5- yl)(methyl)amino]-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 128

3-({[(4R)-7-{methyl[4- (trifluoromethyl)phenyl]amino}-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 129

3-[({7-[phenyl(2,2,2-trifluoroethyl)amino]-3,4- dihydro-2H-1-benzopyran-4- yl}methyl)amino]pyridine-4-carboxylic acid 130

3-({[(1R)-6-[benzyl(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 131

3-({[(4R)-7-[(2,3-dihydro-1H-inden-5- yl)(methyl)amino]-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 132

3-({[(1R)-6-[(1,3-dihydro-2-benzofuran-5- yl)(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 133

3-({[(1R)-6-[cyclopentyl(methyl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 134

3-({[(4R)-7-[(4- cyclopropylphenyl)(methyl)amino]-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 135

3-({[(1R)-6-[(1-benzofuran-6- yl)(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 136

3-({[(4R)-7-[(1-benzofuran-5- yl)(methyl)amino]-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 137

3-({[(1R)-6-[(1-benzofuran-5- yl)(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 138

3-({[(4R)-7-(2-hydroxyphenyl)-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 139

3-({[(4R)-7-[methyl(2-methyl-1,3-thiazol-4- yl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 140

3-({[(1R)-6-[methyl(4-methylphenyl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 141

3-({[(4R)-7-[(1-benzofuran-6- yl)(methyl)amino]-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 142

3-[(3,4-dihydro-1H-2-benzopyran-1- ylmethyl)amino]pyridine-4-carboxylic acid 143

3-({[(1R)-6-[methyl(3-methylphenyl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 144

3-({[(1R)-6-[methyl(thiophen-2-yl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 145

3-({[(4R)-7-[methyl(5-methylpyridin-2- yl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 146

3-[({6-[methyl(phenyl)amino]-3,4-dihydro-1H- 2-benzopyran-1-yl}methyl)amino]pyridine-4- carboxylic acid 147

3-({[(1R)-6-[(2-hydroxyethyl)(phenyl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 148

3-({[(4R)-7-[methyl(6-methylpyridin-2- yl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 149

3-[(1,2,3,4-tetrahydroisoquinolin-1- ylmethyl)amino]pyridine-4-carboxylic acid 150

3-({[(1R)-6-[(3- methoxyphenyl)(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 151

3-({[(4R)-7-[(3-fluoro-4- methylphenyl)(methyl)amino]-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 152

3-({[(4R)-7-[(5-chloropyridin-2- yl)(methyl)amino]-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 153

3-({[(4R)-7-[(5-cyclopropylpyridin-2- yl)(methyl)amino]-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 154

3-({[(4R)-7-[(4-ethylphenyl)(methyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 155

3-({[(1R)-6-[methyl(1-methyl-2-oxo-1,2- dihydropyridin-4-yl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 156

3-({[(1R)-6-[methyl(5-methylpyrimidin-2- yl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 157

3-({[(4R)-7-[(5-ethylpyridin-2- yl)(methyl)amino]-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 158

3-({[(1R)-6-{[4- (hydroxymethyl)phenyl](methyl)amino}- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 159

3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-4- yl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 160

3-({[(1R)-6-{[4- (dimethylamino)phenyl](methyl)amino}- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 161

3-({[(1R)-6-[(4- cyclopropylphenyl)(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 162

3-({[(1R)-6-(2,3,4,5-tetrahydro-1H-1- benzazepin-1-yl)-1,2,3,4-tetrahydronaphthalen- 1-yl]methyl}amino)pyridine-4-carboxylic acid 163

3-({[(1R)-6-[(4-cyclopropylphenyl)(2- methoxyethyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 164

3-({[(1R)-6-{[4- (methoxymethyl)phenyl](methyl)amino}- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 165

3-({[(1R)-6-[(4- hydroxyphenyl)(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 166

3-({[(1R)-6-[(dimethyl-1,2-oxazol-4- yl)(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 167

3-({[(1R)-6-{methyl[4-(pyrrolidin-1- yl)phenyl]amino}-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 168

3-({[(1R)-6-({4-[(1R)-1- hydroxyethyl]phenyl}(methyl)amino)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 169

3-({[(1R)-6-({4-[(1S)-1- hydroxyethyl]phenyl}(methyl)amino)-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 170

3-({[(1R)-6-{methyl[4-(morpholin-4- yl)phenyl]amino}-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 171

3-({[(1R)-6-[methyl(5-methyl-1,2-oxazol-3- yl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 172

3-({[1R)-6-[(2- methoxyphenyl)(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 173

3-({[(1R)-6-[methyl(pyridin-4-yl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 174

3-({[(1R)-6-{[4-(3,6-dihydro-2H-pyran-4- yl)phenyl](methyl)amino}-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 175

3-({[(1R)-6-{methyl[4-(oxan-4- yl)phenyl]amino}-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 176

3-({[(4R)-7-[(4-ethenylphenyl)(methyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 177

3-({[(1R)-6-[(4- methoxyphenyl)(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 178

3-({[(4R)-7-[(4- methxoyphenyl)(methyl)amino]-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 179

3-({[(4R)-7-{methyl[4-(pyrrolidin-1- yl)phenyl]amino}-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 180

3-({[(1R)-6-{[4-(azetidin-1- yl)phenyl](methyl)amino}-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 181

3-({[(1R)-6-{methyl[4- (trifluoromethoxy)phenyl]amino}-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 182

3-({[(4R)-7-{methyl[4- (trifluoromethoxy)phenyl]amino}-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 183

3-({[(4R)-7-{[4-(azetidin-1- yl)phenyl](methyl)amino}3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 184

3-({[(1R)-6-{[4- (difluoromethoxy)phenyl](methyl)amino}- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 185

3-({[(1R)-6-[(4-ethoxyphenyl)(methyl)amino]- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 186

3-({[(4R)-7-[(4-ethoxyphenyl)(methyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 187

3-({[(4R)-7-{methyl[4-(propan-2- yl)phenyl]amino}-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 188

3-({[(1R)-6-{methyl[4-(1H-pyrazol-1- yl)phenyl]amino}-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 189

3-({[(4R)-7-{methyl[4-(1H-pyrazol-1- yl)phenyl]amino}-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 190

3-({[(4R)-7-{[4- (difluoromethoxy)phenyl](methyl)amino}-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 191

3-({[(1R)-6-[methyl(phenyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridazine-4-carboxylic acid 192

3-({[(4R)-7-{methyl[4-(2,2,2- trifluoroethyl)phenyl]amino}-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 193

3-({[(1R)-6-{[4-(1H-imidazol-1- yl)phenyl](methyl)amino}-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 194

3-({[(4R)-7-{[4-(1H-imidazol-1- yl)phenyl](methyl)amino}-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 195

3-({[(1R)-6-{[4-(3,3-difluoroazetidin-1- yl)phenyl](methyl)amino]-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 196

3-({[(4R)-7-{[4-(3,3-difluoroazetidin-1- yl)phenyl](methyl)amino}-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 197

3-({[(1R)-6-{[4-(2- methoxyethoxy)phenyl](methyl)amino}- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 198

3-({[(4R)-7-(1-phenylethyl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 199

3-({[(4R)-7-{methyl[5-(propan-2-yl)pyridin-2- yl]amino}-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 200

3-({[(1R)-6-{[4-(3-hydroxyazetidin-1- yl)phenyl](methyl)amino}-1,2,3,4- tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 201

3-({[(4R)-7-{[4-(3,6-dihydro-2H-pyran-4- yl)phenyl](methyl)amino}-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 202

3-({[(4R)-7-{methyl[4-(oxan-4- yl)phenyl]amino}-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 203

3-({[(4R)-7-(1-phenylcyclopropyl)-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 204

3-({[(4R)-7-{methyl[4-(1-methyl-1,2,3,6- tetrahydropyridin-4-yl)phenyl]amino}-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 205

3-({[(4R)-7-{methyl[4-(1-methylpiperidin-4- yl)phenyl]amino}-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 206

3-({[(4R)-7-[(3,4- dimethylphenyl)(methyl)amino]-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 207

3-({[(4R)-7-{[4-(2- hydroxyethyl)phenyl](methyl)amino}-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 208

3-({[(4R)-7-[methyl(4-propylphenyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 209

3-({[(1R)-6-{[4- (cyclopropylmethoxy)phenyl](methyl)amino}- 1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 210

3-({[(4R)-7-{methyl[4-(propan-2- yloxy)phenyl]amino}-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 211

3-({[(4R)-7-{[4- (cyclopropylmethoxy)phenyl](methyl)amino}- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 212

3-({[(4R)-7-[methyl(4-propoxyphenyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 213

3-({[(4R)-7-[(4- cyclopropoxyphenyl)(methyl)amino]-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 214

3-({[(4R)-7-{methyl[4-(2,2,2- trifluoroethoxy)phenyl]amino}-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 215

3-({[(4R)-7-{[4- (cyclopropylmethyl)phenyl](methyl)amino}- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 216

3-({[(4R)-7-[(4- cyclopropanecarbonylphenyl)(methyl)amino]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 217

3-({[(1S)-5-[methyl(phenyl)amino]-2,3- dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid 218

3-({[(1R)-5-[methyl(phenyl)amino]-2,3- dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid 219

3-({[(1S)-5-[methyl(4-methylphenyl)amino]- 2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid 220

3-({[(1R)-5-[methyl(4-methylphenyl)amino]- 2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid 221

3-({[(1S)-5-{[4- (dimethylamino)phenyl](methyl)amino}-2,3- dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid 222

3-({[(1R)-5-{[4- (dimethylamino)phenyl](methyl)amino}-2,3- dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid 223

3-({[(1S)-5-[(4- cyclopropylphenyl)(methyl)amino]-2,3- dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid 224

3-({[(1R)-5-[(4- cyclopropylphenyl)(methyl)amino]-2,3- dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid 225

3-({[(3S)-6-[methyl(4-methylphenyl)amino]- 2,3-dihydro-1-benzofuran-3- yl]methyl}amino)pyridine-4-carboxylic acid 226

3-({[(3R)-6-[methyl(4-methylphenyl)amino]- 2,3-dihydro-1-benzofuran-3- yl]methyl}amino)pyridine-4-carboxylic acid 227

3-({[(3S)-6-[(4- cyclopropylphenyl)(methyl)amino]-2,3- dihydro-1-benzofuran-3- yl]methyl}amino)pyridine-4-carboxylic acid 228

3-({[(3R)-6-[(4- cyclopropylphenyl)(methyl)amino]-2,3- dihydro-1-benzofuran-3- yl]methyl}amino)pyridine-4-carboxylic acid 229

3-({[(1S)-5-[methyl(4-methylphenyl)amino]- 1,3-dihydro-2-benzofuran-2- yl]methyl}amino)pyridine-4-carboxylic acid 230

3-({[(1R)-5-[methyl(4-methylphenyl)amino]- 1,3-dihydro-2-benzofuran-1- yl]methyl}amino)pyridine-4-carboxylic acid 231

3-({[(1R)-5-[methyl(3-methylphenyl)amino]- 2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid 231

3-({[(1R)-5-[(4-ethylphenyl)(methyl)amino]- 2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid 232

3-({[(1R)-5-{methyl[4-(pyrrolidin-1- yl)phenyl]amino}-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid

In some embodiments, the substituted pyridine derivative compound as described herein, or a stereoisomer or pharmaceutically acceptable salt thereof, has the structure provided in Table 2.

TABLE 2

3-({[(4S)-7-(thiophen-2-yl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-6-(N-methylbenzamido)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-6-(N-methylcyclopropaneamido)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[((1R)-6-(N-methylcyclopentaneamido)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-6-(dimethylamino)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-3- yl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-6-[benzyl(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(5-methylthiophen-2-yl)-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(4-cyanophenyl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(2-cyclopentylethynyl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(3,6-dihydro-2H-pyran-4-yl)-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(4-methoxyphenyl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-[1-(cyclopropylmethyl)-1H-pyrazol-3-yl]- 3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(pyridin-2-yl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(pyridin-3-yl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(2-methyl-1,3-thiazol-5-yl)-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(2-methyl-1,3-thiazol-4-yl)-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(1,2,3,6-tetrahydropyridin-4-yl)-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(piperidin-4-yl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(oxan-4-yl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-742-(1-hydroxycyclopentyl)ethynyl]-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(2-cyanophenyl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(3-cyanophenyl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(4-cyano-2-fluorophenyl)-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(4-cyano-3-fluorophenyl)-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-[4-(trifluoromethoxy)phenyl]-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(4-chlorophenyl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(2-chloro-4-cyanophenyl)-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(3-chloro-4-cyanophenyl)-3,4-dihydro- 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(2,4-difluorophenyl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(5-chlorothiophen-3-yl)-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(5-cyanothiophen-3-yl)-3,4-dihydro-2H-1- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-[5-(trifluoromethyl)thiophen-3-yl]-3,4- benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(5-chlorothiophen-2-yl)-3,4-dihydro-2H- 1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-[5-(trifluoromethyl)thiophen-2-yl]-3,4- dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(5-cyanothiophen-2-yl)-3,4-dihydro-2H-1- benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]- 2,3-dihydro-1-benzofuran-3- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-{methyl[4-(morpholin-4- yl)phenyl]amino}-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-{[4-(3,3-difluoroazetidin-1- yl)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-[(4-methoxyphenyl)(methyl)amino]-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-[(4-methoxyphenyl)(methyl)amino]-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-[(3-methoxyphenyl)(methyl)amino]-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{[4-(azetidin-1- yl)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-{[3- (difluoromethoxy)phenyl](methyl)amino}-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-[(3-ethoxyphenyl)(methyl)amino]-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{methyl[4-(propan-2-yl)phenyl]amino}- 2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{methyl[5-(propan-2-yl)pyridin-2- yl]amino}-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-[methyl(pyridin-2-yl)amino]-2,3-dihydro- 1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-[(6-methoxypyridin-2-yl)(methyl)amino]- 2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-[(2,3-dihydro-1,4-benzodioxin-6- yl)(methyl)amino]-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-[methyl(pyrimidin-4-yl)amino]-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{[4-(3,6-dihydro-2H-pyran-4- yl)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-{methyl[4-(oxan-4-yl)phenyl]amino}-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{methyl[4-(1-methyl-1,2,3,6- tetrahydropyridin-4-yl)phenyl]amino}-2,3-dihydro- 1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-{methyl[4-(1-methylpiperidin-4- yl)phenyl]amino}-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-[methyl(5-methylpyridin-2-yl)amino]-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-[(5-ethylpyridin-2-yl)(methyl)amino]-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{[4-(3-hydroxyazetidin-1- yl)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-{methyl[4-(propan-2- yloxy)phenyl]amino}-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-{[4- (cyclopropylmethoxy)phenyl](methyl)amino}-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{methyl[4-(2,2,2- trifluoroethoxy)phenyl]amino}-2,3-dihydro-1H-inden- 1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-[methyl(4-propoxyphenyl)amino]-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-[(4-cyclopropoxyphenyl)(methyl)amino]- 2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{[4- (cyclopropylmethyl)phenyl](methyl)amino}-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-[(4- cyclopropanecarbonylphenyl)(methyl)amino]-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(3R)-6-{methyl[4-(propan-2-yl)phenyl]amino}- 2,3-dihydro-1-benzofuran-3- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3R)-6-{methyl[4-(propan-2- yloxy)phenyl]amino}-2,3-dihydro-1-benzofuran-3- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-(4-fluorophenyl)-2,3-dihydro-1- benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-(4-cyanophenyl)-2,3-dihydro-1- benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-(thiophen-3-yl)-2,3-dihydro-1- benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-(5-methylthiophen-3-yl)-2,3-dihydro-1- benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-(thiophen-2-yl)-2,3-dihydro-1- benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-(5-methylthiophen-2-yl)-2,3-dihydro-1- benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]- 2,3-dihydro-1-benzofuran-3- yl]methyl}amino)pyridine-4-carboxylic acid

Preparation of the Substituted Pyridine Derivative Compounds

The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), Crescent Chemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.), Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCI America (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.), and Wako Chemicals USA, Inc. (Richmond, Va.).

Methods known to one of ordinary skill in the art are identified through various reference books and databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

Specific and analogous reactants may also be identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., may be contacted for more details). Chemicals that are known but not commercially available in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the substituted pyridine and pyridazine derivative compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

The substituted pyridine derivative compounds are prepared by the general synthetic routes described below in Schemes 1-3.

Referring to Scheme 1, compound A and an amine compound B are mixed and treated under a variety of conditions to form compound C. For example, the mixture of compound A and an amine B can be subjected to microwave irradiation in an appropriate solvent, at temperatures ranging from 120° C. to 172° C. The ester compound E can be prepared from compound C and an alcohol D using a coupling reagent, such as HATU, in the presence of a base.

Referring to Scheme 2, compound F and an aldehyde compound G are mixed and treated under reductive amination conditions to form compound C. The ester compound E can be prepared from compound C and an alcohol D using a coupling reagent, such as HATU, in the presence of a base.

Referring to Scheme 3, compound H and an amine compound B are mixed and treated under a variety of conditions to form compound E. For example, the mixture of compound H and an amine B can be subjected to a Buchwald reaction under microwave irradiation in an appropriate solvent, at temperatures ranging from 100° C. to 120° C. The ester compound E can be hydrolyzed to give compound C, using basic conditions such as 1N aq. NaOH.

Pharmaceutical Compositions

In certain embodiments, the substituted pyridine derivative compound as described herein is administered as a pure chemical. In other embodiments, the substituted pyridine derivative compound as described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, Pa. (2005)), the disclosure of which is hereby incorporated herein by reference, in its entirety.

Accordingly, provided herein is a pharmaceutical composition comprising at least one substituted pyridine derivative compound, or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.

One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formulas (I), (II), (IIa) (III), (IV) or (V) or a tautomer, stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof.

In certain embodiments, the substituted pyridine derivative compound as described by Formulas (I), (II), (IIa) (III), (IV) or (V) is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. Suitable nontoxic solid carriers can be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

The dose of the composition comprising at least one substituted pyridine derivative compound as described herein may differ, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors that a person skilled in the medical art will use to determine dose.

Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated (or prevented) as determined by persons skilled in the medical arts. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the patient.

For the substituted pyridine derivative compounds described herein oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.

Histone Demethylase

Chromatin is the complex of DNA and protein that makes up chromosomes. Histones are the major protein component of chromatin, acting as spools around which DNA winds. Changes in chromatin structure are affected by covalent modifications of histone proteins and by non-histone binding proteins. Several classes of enzymes are known which can covalently modify histones at various sites.

Proteins can be post-translationally modified by methylation on amino groups of lysines and guanidino groups of arginines or carboxymethylated on aspartate, glutamate, or on the C-terminus of the protein. Post-translational protein methylation has been implicated in a variety of cellular processes such as RNA processing, receptor mediated signaling, and cellular differentiation. Post-translational protein methylation is widely known to occur on histones, such reactions known to be catalyzed by histone methyltransferases, which transfer methyl groups from S-adenyosyl methionine (SAM) to histones. Histone methylation is known to participate in a diverse range of biological processes including heterochromatin formation, X-chromosome inactivation, and transcriptional regulation (Lachner et al., (2003) J. Cell Sci. 116:2117-2124; Margueron et al., (2005) Curr. Opin. Genet. Dev. 15:163-176).

Unlike acetylation, which generally correlates with transcriptional activation, whether histone methylation leads to transcription activation or repression depends on the particular site of methylation and the degree of methylation (e.g., whether a particular histone lysine residue is mono-, di-, or tri-methylated). However, generally, methylation on H3K9, H3K27 and H4K20 is linked to gene silencing, while methylation on H3K4, H3K36, and H3K79 is generally associated with active gene expression. In addition, tri- and di-methylation of H3K4 generally marks the transcriptional start sites of actively transcribed genes, whereas mono-methylation of H3K4 is associated with enhancer sequences.

A “demethylase” or “protein demethylase,” as referred to herein, refers to an enzyme that removes at least one methyl group from an amino acid side chain. Some demethylases act on histones, e.g., act as a histone H3 or H4 demethylase. For example, an H3 demethylase may demethylate one or more of H3K4, H3K9, H3K27, H3K36 and/or H3K79. Alternately, an H4 demethylase may demethylate histone H4K20. Demethylases are known which can demethylate either a mono-, di- and/or a tri-methylated substrate. Further, histone demethylases can act on a methylated core histone substrate, a mononucleosome substrate, a dinucleosome substrate and/or an oligonucleosome substrate, peptide substrate and/or chromatin (e.g., in a cell-based assay).

The first lysine demethylase discovered was lysine specific demethylase 1 (LSD1/KDM1), which demethylates both mono- and di-methylated H3K4 or H3K9, using flavin as a cofactor. A second class of Jumonji C (JmjC) domain containing histone demthylases were predicted, and confirmed when a H3K36 demethylase was found using a formaldehyde release assay, which was named JmjC domain containing histone demethylase 1 (JHDM1/KDM2A).

More JmjC domain-containing proteins were subsequently identified and they can be phylogenetically clustered into seven subfamilies: JHDM1, JHDM2, JHDM3, JMJD2, JARID, PHF2/PHF8, UTX/UTY, and JmjC domain only.

JMJD2 Family

The JMJD2 family of proteins are a family of histone-demethylases known to demethylate tri- and di-methylated H3-K9, and were the first identified histone tri-methyl demethylases. In particular, ectopic expression of JMJD2 family members was found to dramatically decrease levels of tri- and di-methylated H3-K9, while increasing levels of mono-methylated H3-K9, which delocalized Heterochromatin Protein 1 (HP1) and reduced overall levels of heterochromatin in vivo. Members of the JMJD2 subfamily of jumonji proteins include JMJD2C and its homologues JMJD2A, JMJD2B, JMJD2D and JMJD2E. Common structural features found in the JMJD2 subfamily of Jumonji proteins include the JmjN, JmjC, PHD and Tdr sequences.

JMJD2C, also known as GASC1 and KDM4C, is known to demethylate tri-methylated H3K9 and H3K36. Histone demethylation by JMJD2C occurs via a hydroxylation reaction dependent on iron and α-ketoglutarate, wherein oxidative decarboxylation of α-ketoglutarate by JMJD2C produces carbon dioxide, succinate, and ferryl and ferryl subsequently hydroxylates a methyl group of lysine H3K9, releasing formaldehyde. JMJD2C is known to modulate regulation of adipogenesis by the nuclear receptor PPARγ and is known to be involved in regulation of self-renewal in embryonic stem cells.

JARID Family

As used herein, a “JARID protein” includes proteins in the JARID subfamily (e.g., JARID1A, JARID1B, JARID1C and JARID1D proteins) and the JARID2 subfamily, as well as homologues thereof. A further description and listing of JARID proteins can be found in Klose et al. (2006) Nature Reviews/Genetics 7:715-727. The JARID1 family contains several conserved domains: JmjN, ARID, JmjC, PHD and a C5HC2 zing finger.

JARID1A, also called KDM5A or RBP2, was initially found as a binding partner of retinoblastoma (Rb) protein. JARID1A was subsequently found to function as a demethylase of tri- and di-methylated H3K4, and has been found to promote cell growth, while inhibiting senescence and differentiation. For instance, abrogation of JARID1A from mouse cells inhibits cell growth, induces senescence and differentiation, and causes loss of pluripotency of embryonic stem cells in vitro. JARID1A has been found to be overexpressed in gastric cancer and the loss of JARID1A has been found to reduce tumorigenesis in a mouse cancer model. Additionally, studies have demonstrated that loss of the retinoblastome binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1 (Lin etal. Proc. Natl. Acad. Sci. USA, Aug. 16, 2011, 108(33), 13379-86; doi: 10.1073/pnas.1110104108) and the authors of the study concluded that RBP2-inhibitory drugs would have anti-cancer activity.

JARID1B, also referred to as KDM5B and PLU1, was originally found in experiments to discover genes regulated by the HER2 tyrosine kinase. JARID1B has consistently been found to be expressed in breast cancer cell lines, although restriction of JARID1B has been found in normal adult tissues, with the exception of the testis. In addition, 90% of invasive ductal carcinomas have been found to express JARID1B. In addition, JARID1B has been found to be up-regulated in prostate cancers, while having more limited expression in benign prostate, and has also been found to be up-regulated in bladder cancer and lung cancer (both SCLC and NSCLC). JARID1B has also been found to repress tumor suppressor genes such as BRCA1, CAV1 and 14-3-3σ, and knockdown of JARID1B was found to increase the levels of tri-methylated H3K4 at these genes.

UTX/UTY Family

UTX/UTY family includes KDM6A, KDM6B, and UTY. KDM6A, also referred to as UTX, and KDM6B, also referred to as JMJD3, act on di- and trimethylated H3K27 and are important for development whereas the substrate and role of UTY remains to be elucidated. Both KDM6A (UTX) and KDM6B (JMJD3) have demonstrated tumor-suppressive characteristics by functioning as antagonists to the oncogenic polycomb (PcG) proteins. PcG proteins are important repressive histone marks that catalyze the tri- and dimethylation of H3K27 The PcG genes have been characterized as oncogenes that are frequently overexpressed or amplified in cancer.

In an additional embodiment is the method for inhibiting a histone-demethylase enzyme comprising contacting the enzyme with a substituted pyridine derivative compound as disclosed herein, wherein the histone-demethylase enzyme comprises a JmjC domain. In an additional embodiment is the method for inhibiting a histone-demethylase enzyme comprising contacting the enzyme with a substituted pyridine derivative compound as disclosed herein, wherein the histone-demethylase enzyme is selected from JARID1A, JARID1B, or JMJD2C. In an additional embodiment is the method for inhibiting a histone-demethylase enzyme comprising contacting the enzyme with a substituted pyridine derivative compound as disclosed herein, wherein the histone-demethylase enzyme is selected from JARID1A, JARID1B, JMJD2C, and JMJD3. In one embodiment is the method for inhibiting the histone-demethylase enzyme JMJD3 comprising contacting the JMJD3 enzyme with a substituted pyridine derivative compound as disclosed herein. In one embodiment is the method for inhibiting the histone-demethylase enzyme JMJD2C comprising contacting the JMJD2C enzyme with a substituted pyridine derivative compound as disclosed herein.

Methods of Treatment

Disclosed herein are methods of modulating demethylation in a cell or in a subject, either generally or with respect to one or more specific target genes. Demethylation can be modulated to control a variety of cellular functions, including without limitation: differentiation; proliferation; apoptosis; tumorigenesis, leukemogenesis or other oncogenic transformation events; hair loss; or sexual differentiation. For example, in particular embodiments, provided herein is a method of treating a disease regulated by histone methylation and/or demethylation in a subject in need thereof by modulating the activity of a demethylase comprising a JmjC domain (e.g., a histone demethylase such as a JHDM protein(s)).

In one embodiment is provided a method of treating cancer in a patient in need thereof comprising administering to the patient a composition comprising a compound of Formula (I), (II), (IIa) (III), (IV) or (V) or a pharmaceutically acceptable salt thereof. In a further embodiment is the method for treating cancer in a patient wherein the cancer is selected from prostate cancer, breast cancer, bladder cancer, lung cancer or melanoma.

In an additional embodiment is a method for inhibiting the growth of a tumor comprising exposing the tumor to a composition comprising a compound of Formula (I), (II), (IIa) (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, wherein the tumor is characterized by a loss of retinoblastoma gene (RB1) function.

In an additional embodiment is a method for inhibiting the growth of a tumor comprising exposing the tumor to a composition comprising a compound of Formula (I), (II), (IIa) (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, wherein the tumor is characterized by a loss of multiple endocrine neoplasia type 1 gene (Men1) function.

Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.

EXAMPLES I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and/or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (δ) and coupling constants, J are reported in Hertz. For proton spectra the solvent peak was used as the reference peak.

Preparation 1a: 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one

A solution of NaNO₂ (2.35 g, 34 mmol) in water (10 mL) was added dropwise to the solution of 6-amino-1,2,3,4-tetrahydronaphthalen-1-one (5.0 g, 31 mmol) in 25% HBr (16 mL) at 0° C. The suspension was then transferred to a stirred mixture of CuBr (8.9 g, 62 mmol) in 48% HBr (30 mL) at 0° C. The resulting mixture was allowed to warm to rt and stirred for 1 h. The mixture was extracted with EtOAc, dried (Na₂SO₄), and concentrated. The residue was purified by silica gel chromatography (0%-60% EtOAc/Hex) to give 5.6 g (80%) of the title compound as a light yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 2.10-2.16 (2H, m), 2.64 (2H, t, J=6.4 Hz), 2.94 (2H, t, J=6.0 Hz), 7.42 (1H, s), 7.44 (1H, s), 7.87 (1H, d, J=8.9 Hz). [M+H] calc'd for C₁₀H₉BrO, 225, 227; found 225, 227.

Preparation 1b: 6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (2.0 g, 8.9 mmol) in toluene (20 mL) was added N-methylaniline (960 mg, 8.9 mmol), Cs₂CO₃ (4.4 g, 13.4 mmol), BINAP (310 mg, 0.5 mmol) and Pd(OAc)₂ (110 mg, 0.5 mmol). The mixture was stirred overnight at 100° C. under nitrogen. The mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (30%-80% EtOAc/Hex) to give 1.52 g (68%) of the title compound as a light brown oil. [M+H] calc'd for C₁₇H₁₇NO, 252; found 252.

Preparation 1c: 5-(aminomethyl)-N-methyl-N-phenyl-7,8-dihydronaphthalen-2-amine, Hydrochloride

To a solution of Preparation 1b (1.52 g, 6.0 mmol) and ZnI₂ (150 mg) in toluene (20 mL) was added TMSCN (1.2 g, 12 mmol) at rt. The mixture was heated at 60° C. for 2 h. The reaction mixture was cooled to rt and diluted with addition of THF (20 mL). A solution of LAH (5 mL, 2.4 M in THF, 12 mmol) was added slowly at rt, and the solution stirred for 0.5 h. The reaction was quenched with the addition of EtOAc (10 mL), and then water (1 mL) and aqueous 1 M NaOH (1 mL). The solution was dried (Na₂SO₄) and concentrated to give 1.52 g (89%) of the crude 1-(aminomethyl)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-ol as a white solid.

Into a solution of this intermediate (1.52 g, 5.4 mmol) in methanol (20 mL) was bubbled dry HCl gas for 2 min, while the reaction was cooled so as to not allow the temperature to exceed 30° C. The mixture was then stirred at rt for 1 h. The methanol was evaporated under reduced pressure to give 1.4 g (98%) of the title compound as the HCl salt. [M+H] calc'd for C₁₈H₂₀N₂, 265; found 265.

Preparation 1d: 5-(aminomethyl)-N-methyl-N-phenyl-5,6,7,8-tetrahydronaphthalen-2-amine

To a solution of Preparation 1c (1.4 g, 5.3 mmol) in MeOH (30 mL) and conc. HCl (three drops) was added 10% Pd/C (200 mg) at rt under N₂. The suspension was stirred at rt for 16 h under hydrogen at 50 psi. The reaction mixture was filtered through Celite, adjusted to pH=8˜9 with sat. Na₂CO₃, dried (Na₂SO₄), and concentrated to give 830 mg (59%) of the title compound as a yellow oil. [M+H] calc'd for C₁₈H₂₂N₂, 267; found 267.

Preparation 1e: methyl 3-[({6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)amino]pyridine-4-carboxylate

To a solution of Preparation 1d (500 mg, 1.88 mmol) in DMA (12 mL) was added methyl 3-fluoroisonicotinate (300 mg, 1.93 mmol). The reaction mixture was stirred at 170° C. for 1 h in a microwave. The reaction mixture was poured into water and extracted with EtOAc. Organics were washed with brine, dried (Na₂SO₄), and concentrated. The residue was purified by silica gel chromatography (20-80% EtOAc/Hex) to give 200 mg (26%) of the title compound as a yellow oil. [M+H] calc'd for C₂₅H₂₇N₃O₂, 402; found 402.

Preparation 1f: methyl 3-({[(1S)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate, and Preparation 2f: methyl 3-({[(1R)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

Preparation 1e (200 mg) was separated by chiral HPLC (Column: Chiralcel IA, 250 mm*4.6 mm 5 um; Mobile phase: Hex:EtOH=85:15; F: 1.0 mL/min; W: 230 nm; T=30° C.) to give 95 mg (47%) of Preparation if (6.54 min) and 92 mg (46%) of Preparation 2f (7.91 min), each as a yellow oil.

Example 1: 3-({[(1S)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

To a solution of Preparation if (95 mg, 0.24 mmol) in THF (6 mL) and H₂O (2 mL) was added LiOH.H₂O (31 mg, 0.72 mmol) at rt, and the reaction mixture was stirred overnight. The reaction mixture was concentrated to remove THF, and the residue was diluted with water and acidified to pH=3˜4 with 1.0 N aqueous HCl solution. The precipitate was collected by filtration and washed with EtOAc/ether. The solid was dried under vacuum to give 52 mg (56%) of the title compound as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.64-1.67 (1H, m), 1.77-1.84 (3H, m), 2.65-2.68 (2H, d, J=5.6 Hz), 3.04-3.07 (1H, m), 3.21 (3H, s), 3.41-3.47 (1H, m), 3.56-3.60 (1H, m), 6.78-6.92 (5H, m), 7.21-7.25 (3H, m), 7.55 (1H, d, J=5.2 Hz), 7.82 (1H, d, J=5.2 Hz), 8.36 (1H, s). [M+H] Calc'd for C₂₄H₂₅N₃O₂, 388; Found, 388.

Example 2: 3-({[(1R)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 53% yield from Preparation 2f according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.64-1.68 (1H, m), 1.77-1.84 (3H, m), 2.65-2.68 (2H, d, J=5.6 Hz), 3.04-3.07 (1H, m), 3.21 (3H, s), 3.41-3.47 (1H, m), 3.56-3.60 (1H, m), 6.78-6.92 (5H, m), 7.21-7.25 (3H, m), 7.56 (1H, d, J=4.8 Hz), 7.82 (1H, d, J=5.2 Hz), 8.36 (1H, s). [M+H] calc'd for C₂₄H₂₅N₃O₂, 388; found 388.

Preparation 3a: (6-bromo-3,4-dihydronaphthalen-1-yl)methanamine, Hydrochloride

To a solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (5.00 g, 22.0 mmol) and ZnI₂ (300 mg) in toluene (50 mL) was added TMSCN (4.36 g, 44.0 mmol) at rt. The mixture was heated at 60° C. overnight. The reaction mixture was cooled to rt, and a solution of LAH (20.0 mL, 2.4 M in THF, 44.0 mmol) was added slowly. The reaction stirred at 40° C. for 2 h. The reaction was cooled to 0° C. was quenched with addition of EtOAc (10 mL) at 0° C., and then water (5 mL) and aqueous 10% NaOH (5 mL). The mixture was filtered through Celite and concentrated to give the 4.5 g (79%) of the crude 1-(aminomethyl)-6-bromo-1,2,3,4-tetrahydronaphthalen-1-ol intermediate as a brown oil. To a solution of this intermediate (4.5 g, 17.4 mmol) in toluene (100 mL) was added 4N HCl/dioxane (20 mL) solution, and the mixture was stirred at reflux for 10 min. The mixture was cooled to room temperature and concentrated to give 3.6 g (75%) of the title compound as a tan solid. [M+H] calc'd for C₁₁H₁₂BrN, 237, 239; found 237, 239.

Preparation 3b: tert-butyl N-[(6-bromo-3,4-dihydronaphthalen-1-yl)methyl]carbamate

To a solution of Preparation 3a (1.05 g, 3.84 mmol) in DCM (10 mL) was added TEA (1.6 mL, 11.5 mmol), Boc₂O (2.1 g, 9.6 mmol) and DMAP (94 mg, 0.77 mmol). The mixture was stirred at rt for 1 h. The reaction was concentrated, and the residue was purified by silica gel chromatography (20-60% EtOAc/Hex) to give 900 mg (69%) of the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 1.44 (9H, s), 2.24-2.29 (2H, m), 2.70-2.74 (2H, m), 4.12 (2H, d, J=4.8 Hz), 4.56 (1H, br s), 6.03 (1H, t, J=4.4 Hz), 7.10 (1H, d, J=8.0 Hz), 7.26-7.32 (2H, m).

Preparation 3c: tert-butyl N-{[6-(2-oxopyrrolidin-1-yl)-3,4-dihydronaphthalen-1-yl]methyl}carbamate

To a solution of Preparation 3b (900 mg, 2.67 mmol) in dioxane (10 mL) was added 2-pyrrolidinone (680 mg, 8.0 mmol), Cs₂CO₃ (1.3 g, 4.0 mmol), BINAP (283 mg, 0.45 mmol) and Pd(OAc)₂ (60 mg, 0.27 mmol). The mixture was stirred at 100° C. for 4 h under nitrogen. The mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (30-80% EtOAc/Hex) to give 470 mg (51%) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.38 (9H, s), 2.01-2.08 (2H, m), 2.18-2.23 (2H, m), 2.45-2.50 (2H, m), 2.68 (2H, t, J=8.0 Hz), 3.81 (2H, t, J=7.0 Hz), 3.92 (2H, d, J=4.8 Hz), 5.86 (1H, s), 7.02 (1H, t, J=5.4 Hz), 7.22 (1H, d, J=8.8 Hz), 7.42 (1H, d, J=8.4 Hz), 7.48 (1H, s).

Preparation 3d: 1-[5-(aminomethyl)-7,8-dihydronaphthalen-2-yl]pyrrolidin-2-one, Hydrochloride

A solution of Preparation 3c (470 mg, 1.37 mmol) in 4 N HCl/dioxane (10 mL) was stirred overnight at rt. The mixture was concentrated to 330 mg (99%) of the title compound as a tan oil. ¹H NMR (400 MHz, MeOD-d₄): δ 2.19-2.23 (2H, m), 2.38-2.41 (2H, m), 2.63 (2H, t, J=8.2 Hz), 2.84 (2H, t, J=8.2 Hz), 3.96 (2H, t, J=7.0 Hz), 4.02 (2H, s), 6.26 (1H, t, J=4.4 Hz), 7.31 (1H, d, J=8.8 Hz), 7.52 (1H, s), 7.54 (1H, d, J=6.8 Hz). [M+H] calc'd for C₁₅H₁₈N₂O, 243; found 243.

Preparation 3e: 1-[5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]pyrrolidin-2-one

To a solution of Preparation 3d (330 mg, 1.36 mmol) in MeOH (10 mL) and conc. HCl (one drop) was added 10% Pd/C (50 mg) at rt under N₂. The suspension was stirred overnight under hydrogen at 50 psi. The reaction mixture was filtered through Celite, adjusted to pH=8˜9 with sat. Na₂CO₃, dried (Na₂SO₄), and concentrated to give 240 mg (72%) of the title compound as a white solid. [M+H] calc'd for C₁₅H₂₀N₂O, 245; found 245.

Preparation 3f: methyl 3-({[6-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 15% yield from Preparation 3e according to the general procedure for Preparation 1e. [M+H] calc'd for C₂₂H₂₅N₃O₃, 380; found 380.

Example 3: 3-({[6-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 92% yield from Preparation 3f according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.65-1.69 (1H, m), 1.78-1.84 (3H, m), 2.00-2.07 (2H, m), 2.44-2.50 (2H, m), 2.70-2.73 (2H, m), 3.06-3.10 (1H, m), 3.38-3.45 (1H, m), 3.54-3.58 (1H, m), 3.79 (2H, t, J=7.0 Hz), 7.29 (1H, d, J=8.0 Hz), 7.34 (1H, s), 7.41 (1H, d, J=8.0 Hz), 7.55 (1H, d, J=5.2 Hz), 7.81 (1H, d, J=5.2 Hz), 8.34 (1H, s). [M+H] calc'd for C₂₁H₂₃N₃O₃, 366; found 366.

Preparation 4a: 6-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl 4-methylbenzene-1-sulfonate (1.0 g, 3.4 mmol) in THF (20 mL) was added 1,2,3,4-tetrahydroquinoline (0.55 g, 4.1 mmol), Pd(OAc)₂ (92 mg, 0.41 mmol), BINAP (383 mg, 0.61 mmol) and Cs₂CO₃ (1.7 g, 5.1 mmol). The mixture was heated to reflux under nitrogen overnight. The mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (10% EtOAc/hexanes) to give 0.72 g (76%) of the title compound as a brown oil. ¹H NMR (400 MHz, CDCl₃): δ 7.94 (d, J=8.4 Hz, 1H), 7.18-7.04 (m, 4H), 6.97 (d, J=2.4 Hz, 1H), 6.90 (dt, J=7.6 Hz, 1.2 Hz, 1H), 3.69 (t, J=6.0 Hz, 2H), 2.87 (t, J=6.0 Hz, 2H), 2.77 (t, J=6.4 Hz, 2H), 2.61 (t, J=6.4 Hz, 2H), 2.14-2.08 (m, 2H), 2.05-1.98 (m, 2H). [M+H] calc'd for C₁₉H₁₉NO, 278; found 278.

Preparation 4b: [6-(1,2,3,4-tetrahydroquinolin-1-yl)-3,4-dihydronaphthalen-1-yl]methanamine, Hydrochloride

The title compound was prepared in 65% yield from Preparation 4a according to the general procedure for Preparation 3a. [M+H] calc'd for C₂₀H₂₂N₂, 291; found 291.

Preparation 4c: [6-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 96% yield from Preparation 4b according to the general procedure for Preparation 3e, except that the reaction was heated at 50° C. [M+H] calc'd for C₂₀H₂₄N₂, 293; found 293.

Preparation 4d: methyl 3-({[6-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 4c (0.49 g, 1.7 mmol) in toluene (10 mL) was added methyl 3-bromoisonicotinate (0.36 g, 1.7 mmol), Pd₂(dba)₃ (31 mg, 0.033 mmol), Xantphos (58 mg, 0.1 mmol) and Cs₂CO₃ (0.76 g, 2.3 mmol). The mixture was heated to reflux under nitrogen overnight. The mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (10-30% EtOAc/Hex) to give 0.35 g (49%) of the title compound as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.34 (s, 1H), 7.91 (d, J=5.2 Hz, 1H), 7.63 (d, J=5.2 Hz, 1H), 7.61-7.58 (m, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.05-6.99 (m, 2H), 6.93 (dd, J=8.0 Hz 7.6 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.68 (t, J=7.6 Hz, 1H), 3.90 (s, 3H), 3.64-3.58 (m, 3H), 3.47-3.40 (m, 1H), 3.19-3.13 (m, 1H), 2.84 (t, J=6.4 Hz, 2H), 2.78-2.74 (m, 2H), 2.06-2.00 (m, 2H), 1.97-1.75 (m, 4H). [M+H] calc'd for C₂₇H₂₉N₃O₂, 428; found 428.

Example 4: 3-({[6-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 21% yield from Preparation 4d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 8.35 (s, 1H), 7.82 (d, J=4.4 Hz, 1H), 7.56 (d, J=4.4 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.01-6.93 (m, 3H), 6.86 (dd, J=7.6 Hz, 8.0 Hz, 1H), 6.61 (dd, J=7.6 Hz, 7.2 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 3.62-3.51 (m, 3H), 3.47-3.40 (m, 1H), 3.11-3.06 (m, 1H), 2.78-2.66 (m, 4H), 1.94-1.78 (m, 6H). [M+H] calc'd for C₂₆H₂₇N₃O₂, 414; found 414.

Preparation 5a: 6-(2,3-dihydro-1H-indol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 93% yield using indoline according to the general procedure for Preparation 4a. [M+H] calc'd for C₁₈H₁₇NO, 264; found 264.

Preparation 5b: [6-(2,3-dihydro-1H-indol-1-yl)-3,4-dihydronaphthalen-1-yl]methanamine, Hydrochloride

The title compound was prepared in 77% yield from Preparation 5a according to the general procedure for Preparation 3a. [M+H] calc'd for C₁₉H₂₀N₂, 277; found 277.

Preparation 5c: [6-(2,3-dihydro-1H-indol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 97% yield from Preparation 5b according to the general procedure for Preparation 3e, except the reaction was heated at 50° C. [M+H] calc'd for C₁₉H₂₂N₂, 279; found 279.

Preparation 5d: methyl 3-({[6-(2,3-dihydro-1H-indol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 24% yield from Preparation 5c according to the general procedure for Preparation 1e. [M+H] calc'd for C₂₆H₂₇N₃O₂, 414; found 414.

Example 5: 3-({[6-(2,3-dihydro-1H-indol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 78% yield from Preparation 5d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.67-2.88 (4H, m), 2.71-2.77 (2H, m), 3.03-3.10 (3H, m), 3.42-3.49 (1H, m), 3.56-3.58 (1H, m), 3.88 (2H, t, J=8.4 Hz), 6.67-6.71 (1H, m), 6.93-6.94 (1H, m), 7.02-7.04 (3H, m), 7.15 (1H, d, J=7.2 Hz), 7.29 (1H, d, J=8.4 Hz), 7.59 (1H, d, J=8.1 Hz), 8.84 (1H, d, J=4.8 Hz), 8.39 (1H, s). [M+H] calc'd for C₂₅H₂₅N₃O₂, 400; found 400.

Preparation 6a: 6-bromo-3,4-dihydronaphthalene-1-carboxamide

To a solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (5.46 g, 24.3 mmol) and ZnI₂ (50 mg) in toluene (50 mL) was added TMSCN (4.82 mL, 48.6 mmol), and the solution stirred at 60° C. overnight. The reaction was cooled to rt, and H₂SO₄ (5.6 mL) was added. Then AcOH (34 mL), H₂SO₄ (25 mL) and H₂O (4 mL) were added to the reaction, and it was heated to 105° C. for 3 h. The mixture was cooled and poured over ice-water (250 mL). The precipitate was collected by filtration, washed with water, and dried under vacuum to give 4.88 g (80%) of the title compound as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 2.25-2.33 (2H, m), 2.72 (2H, t, J=8.0 Hz), 6.51 (1H, t, J=4.6 Hz), 7.20 (1H, br s), 7.35-7.40 (3H, m), 7.65 (1H, br s). [M+H] calc'd for C₁₁H₁₀BrNO, 252, 254; found 252, 254.

Preparation 6b: (1R)-6-bromo-1,2,3,4-tetrahydronaphthalene-1-carboxamide

To a solution of Preparation 6a (4.88 g, 19.4 mmol) in MeOH (75 mL) and THF (75 mL) was added Ru(OAc)₂[s-binap] (82 mg, 0.097 mmol). The mixture was heated at 40° C. under hydrogen at 120 psi overnight. The solution was concentrated to give the crude title compound (ee>80%). Re-crystallization from ACN gave 3.8 g (77%) of the title compound (ee>96%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.55-1.62 (1H, m), 1.85-1.94 (3H, m), 2.67-2.74 (2H, m), 3.56 (1H, t, J=6.6 Hz), 6.98 (1H, br s), 7.02 (1H, d, J=8.9 Hz), 7.25-7.29 (2H, m), 7.47 (1H, br s). [M+H] calc'd for C₁₁H₁₂BrNO, 254, 256; found 254, 256. Analytical Column: Chiralcel: AS-H, Mobile phase: Hex:EtOH=60:40.

Preparation 6c: [(1R)-6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

To a solution of Preparation 6b (2.5 g, 9.84 mmol) in THF (40 mL) was added BH₃.THF (39.4 mL, 1.0 M in THF, 39.4 mmol) at rt, and the solution was heated at 55° C. overnight. The solution was cooled and quenched with 10% H₂SO₄ (8 mL) and stirred for 6 h. The solution was made basic with aq. NH₄OH and extracted (3×) with EtOAc. Organics were dried (Na₂SO₄) and concentrated to give 2.36 g (100%) of the crude title compound as a brown oil. [M+H] calc'd for C₁₁H₁₄BrN, 240, 242; found 240, 242.

Preparation 6d: tert-butyl N-{[(1R)-6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a solution of Preparation 6c (2.36 g, 9.83 mmol) and DIEA (2.23 mL, 12.8 mmol) in DCM (50 mL) was added (Boc)₂O (2.58 g, 11.8 mmol), and the reaction stirred at rt for 2 h. The solution was washed with brine, dried (MgSO₄), and concentrated. Purification by silica gel chromatography (10-60% EtOAc/Hex) gave 3.02 g (90%) of the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 1.45 (9H, s), 1.72-1.85 (4H, m), 2.69-2.75 (2H, m), 2.88-2.96 (1H, m), 3.21-3.27 (1H, m), 3.35-3.42 (1H, m), 4.61 (1H, br s), 7.08 (1H, d, J=7.4 Hz), 7.22-7.27 (2H, m). [M+H] calc'd for C₁₆H₂₂BrNO₂, 340, 342; found 340, 342.

Preparation 6e: tert-butyl N-{[(1R)-6-[(2-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a suspension of Preparation 6d (150 mg, 0.442 mmol), 2-fluoro-N-methylaniline (83 mg, 0.66 mmol), BINAP (14 mg, 0.022 mmol) and Cs₂CO₃ (216 mg, 0.664 mmol) in toluene (10 mL) was added Pd(OAc)₂ (3 mg, 0.01 mmol) at rt under N₂. The reaction was stirred at 105° C. overnight. The mixture was filtered and concentrated. Purification by silica gel chromatography (PE:EtOAc=8:1) gave 105 mg (62%) of the title compound as a brown oil. [M+H] calc'd for C₂₃H₂₉FN₂O₂, 385; found 385.

Preparation 6f: (5R)-5-(aminomethyl)-N-(2-fluorophenyl)-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

To a solution of Preparation 6e (105 mg, 0.273 mmol) in EtOAc (5 mL) was added HCl/EtOAc (5 mL, 1.0 M), and the reaction was stirred at rt for 30 min. The solution was concentrated, re-dissolved in EtOAc, and washed with sat. Na₂CO₃. The organic layer was dried (Na₂SO₄) and concentrated to give 79 mg (100%) of the title compound as a yellow oil. [M+H] calc'd for C₁₈H₂₁FN₂, 285; found 285.

Preparation 6g: methyl 3-({[(1R)-6-[(2-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 60% yield from Preparation 6f according to the general procedure for Preparation 4d. [M+H] calc'd for C₂₅H₂₆FN₃O₂, 420; found 420.

Example 6: 3-({[(1R)-6-[(2-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 79% yield from Preparation 6g according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.62-1.83 (4H, m), 2.61-2.63 (2H, m), 2.98-3.02 (1H, m), 3.20 (3H, s), 3.34-3.41 (1H, m), 3.50-3.55 (1H, m), 6.44-6.48 (2H, m), 7.13 (1H, d, J=8.4 Hz), 7.22-7.33 (4H, m), 7.56 (1H, d, J=5.2 Hz), 7.82 (1H, d, J=4.8 Hz), 8.34 (1H, s). [M+H] calc'd for C₂₄H₂₄FN₃O₂, 406; found 406.

Preparation 7a: tert-butyl N-{[(1R)-6-[(3-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 56% yield from Preparation 6d and 3-fluoro-N-methylaniline according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₃H₂₉FN₂O₂, 385; found 385.

Preparation 7b: (5R)-5-(aminomethyl)-N-(3-fluorophenyl)-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation 7a according to the general procedure for Preparation 6f. [M+H] calc'd for C₁₈H₂₁FN₂, 285; found 285.

Preparation 7c: methyl 3-({[(1R)-6-[(3-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 66% yield from Preparation 7b according to the general procedure for Preparation 4d. [M+H] calc'd for C₂₅H₂₆FN₃O₂, 420; found 420.

Example 7: 3-({[(1R)-6-[(3-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 76% yield from Preparation 7c according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.67-1.86 (4H, m), 2.69-2.72 (2H, m), 3.09-3.12 (1H, m), 3.31 (3H, s), 3.44-3.50 (1H, m), 3.59-3.64 (1H, m), 6.51-6.58 (3H, m), 6.92-6.95 (2H, m), 7.14-7.20 (1H, m), 7.33 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=5.2 Hz), 7.84 (1H, d, J=5.2 Hz), 8.38 (1H, s). [M+H] calc'd for C₂₄H₂₄FN₃O₂, 406; found 406.

Preparation 8a: tert-butyl N-{[(1R)-6-[(4-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 76% yield from Preparation 6d and 4-fluoro-N-methylaniline according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₃H₂₉FN₂O₂, 385; found 385.

Preparation 8b: (5R)-5-(aminomethyl)-N-(4-fluorophenyl)-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation 8a according to the general procedure for Preparation 6f. [M+H] calc'd for C₁₈H₂₁FN₂, 285; found 285.

Preparation 8c: methyl 3-({[(1R)-6-[(4-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 42% yield from Preparation 8b according to the general procedure for Preparation 4d. [M+H] calc'd for C₂₅H₂₆FN₃O₂, 420; found 420.

Example 8: 3-({[(1R)-6-[(4-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 78% yield from Preparation 8c according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.63-1.67 (1H, m), 1.75-1.85 (3H, m), 2.63-2.68 (2H, m), 3.02-3.06 (1H, m), 3.19 (3H, s), 3.39-3.45 (1H, m), 3.53-3.59 (1H, m), 6.68-6.73 (2H, m), 6.97-7.02 (2H, m), 7.07-7.13 (2H, m), 7.20 (1H, d, J=8.3 Hz), 7.56 (1H, d, J=5.0 Hz), 7.69 (1H, br s), 7.82 (1H, d, J=5.0 Hz), 8.34 (1H, s), 13.36 (1H, br s). [M+H] calc'd for C₂₄H₂₄FN₃O₂, 406; found 406.

Preparation 9a: tert-butyl N-{[(1R)-6-[(4-chlorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a solution of Preparation 6d (200 mg, 0.59 mmol) in toluene (5 mL) was added 4-chloro-N-methylaniline (100 mg, 0.7 mmol), Pd₂(dba)₃ (27 mg, 0.03 mmol), Xantphos (51 mg, 0.15 mmol) and NaOtBu (68 mg, 0.7 mmol). The mixture was heated at 96° C. in a microwave for 1 h. The mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give 168 mg (76%) of the title compound as a pale yellow solid. [M+H] calc'd for C₂₃H₂₉ClN₂O₂, 401; found 401.

Preparation 9b: (5R)-5-(aminomethyl)-N-(4-chlorophenyl)-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

Preparation 9a (168 mg, 0.42 mmol) was stirred in 50% TFA/DCM for 1 h. The solution was concentrated, and the residue was dissolved in EtOAc and washed with sat. NaHCO₃, dried (Na₂SO₄) and concentrated to give 126 mg (quantitative) clear oil. [M+H] calc'd for C₁₈H₂₁ClN₂, 301; found 301.

Preparation 9c: methyl 3-({[(1R)-6-[(4-chlorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 12% yield from Preparation 9b according to the general procedure for Preparation 4d. [M+H] calc'd for C₂₅H₂₆ClN₃O₂, 436; found 436.

Example 9: 3-({[(1R)-6-[(4-chlorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 76% yield from Preparation 9c according to the general procedure for Example 1. ¹H NMR (400 MHz, MeOD): δ 1.73-1.79 (1H, m), 1.90-1.97 (3H, m), 2.73-2.81 (2H, m), 3.12-3.15 (1H, s), 3.23 (3H, s), 3.42-3.48 (1H, m), 3.54-3.59 (1H, m), 6.81-6.85 (4H, m), 7.15 (2H, dd, J=6.8, 2.2 Hz), 7.21 (1H, d, J=8.1 Hz), 7.76-7.82 (2H, m), 8.21 (1H, s). [M+H] calc'd for C₂₄H₂₄ClN₃O₂, 422; found 422.

Preparation 10a: tert-butyl N-{[(1R)-6-[ethyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 59% yield from Preparation 6d and N-ethylaniline according to the general procedure for Preparation 9a. [M+H] calc'd for C₂₄H₃₂N₂O₂, 381; found 381.

Preparation 10b: (5R)-5-(aminomethyl)-N-ethyl-N-phenyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation 10a according to the general procedure for Preparation 9b. [M+H] calc'd for C₁₉H₂₄N₂, 281; found 281.

Preparation 10c: methyl 3-({[(1R)-6-[ethyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 82% yield from Preparation 10b according to the general procedure for Preparation 4d. [M+H] calc'd for C₂₆H₂₉N₃O₂, 416; found 416.

Example 10: 3-({[(1R)-6-[ethyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 90% yield from Preparation 10c according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.11 (3H, t, J=7.0 Hz), 1.63-1.83 (4H, m), 2.62-2.70 (2H, m), 3.03-3.07 (1H, m), 3.39-3.46 (1H, m), 3.55-3.61 (1H, m), 3.70 (2H, q, J=7.0 Hz), 6.75-6.89 (5H, m), 7.19-7.25 (3H, m), 7.56 (1H, d, J=5.0 Hz), 7.69 (1H, br s), 7.82 (1H, d, J=5.0 Hz), 8.34 (1H, s), 13.47 (1H, br s). [M+H] calc'd for C₂₅H₂₇N₃O₂, 402; found 402.

Preparation 11a: tert-butyl N-{[(1R)-6-[methyl(pyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 41% yield from Preparation 6d and N-methyl-2-pyridinamine according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₂H₂₉N₃O₂, 368; found 368.

Preparation 11b: N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-methylpyridin-2-amine

The title compound was prepared in 99% yield from Preparation 11a according to the general procedure for Preparation 6f. [M+H] calc'd for C₁₇H₂₁N₃, 268; found 268.

Preparation 11c: methyl 3-({[(1R)-6-[methyl(pyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 42% yield from Preparation 11b according to the general procedure for Preparation 4d. [M+H] calc'd for C₂₄H₂₆N₄O₂, 403; found 403.

Example 11: 3-({[(1R)-6-[methyl(pyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 32% yield from Preparation 11c according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.67-1.71 (1H, m), 1.80-1.88 (3H, m), 2.70-2.74 (2H, m), 3.02-3.05 (1H, m), 3.23-3.29 (1H, m), 3.40 (3H, s), 3.47-3.50 (1H, m), 6.48 (1H, d, J=8.8 Hz), 6.61-6.64 (1H, m), 7.00 (1H, s), 7.02 (1H, d, J=8.0 Hz), 7.37-7.41 (2H, m), 7.54 (1H, d, J=4.8 Hz), 7.68 (1H, d, J=4.8 Hz), 8.05 (1H, s), 8.13 (1H, d, J=4.8 Hz), 9.19 (1H, br s). [M+H] calc'd for C₂₃H₂₄N₄O₂, 389; found 389.

Preparation 12a: tert-butyl N-{[(1R)-6-[methyl(pyridin-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 77% yield from Preparation 6d and N-methyl-3-pyridinamine according to the general procedure for Preparation 9a. [M+H] calc'd for C₂₂H₂₉N₃O₂, 368; found 368.

Preparation 12b: N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-methylpyridin-3-amine

The title compound was prepared in 88% yield from Preparation 12a according to the general procedure for Preparation 9b. [M+H] calc'd for C₁₇H₂₁N₃, 268; found 268.

Preparation 12c: methyl 3-({[(1R)-6-[methyl(pyridin-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 27% yield from Preparation 12b according to the general procedure for Preparation 4d. [M+H] calc'd for C₂₄H₂₆N₄O₂, 403; found 403.

Example 12: 3-({[(1R)-6-[methyl(pyridin-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 62% yield from Preparation 12c according to the general procedure for Example 1. ¹H NMR (400 MHz, MeOD): δ 1.75-1.79 (1H, m), 1.93-1.99 (3H, m), 2.72-2.81 (2H, m), 3.19-3.23 (1H, m), 3.33 (3H, s), 3.50-3.63 (2H, m), 6.91-6.97 (2H, m), 7.30-7.38 (3H, m), 7.76-7.82 (2H, m), 7.92 (1H, br s), 8.04 (1H, br s), 8.15 (1H, s). [M+H] calc'd for C₂₃H₂₄N₄O₂, 389; found 389.

Preparation 13a: tert-butyl N-{[(1R)-6-[(6-methoxypyridin-3-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 64% yield from Preparation 6d and 6-methoxy-N-methylpyridin-3-amine according to the general procedure for Preparation 9a. [M+H] calc'd for C₂₃H₃₁N₃O₃, 398; found 398.

Preparation 13b: N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-6-methoxy-N-methylpyridin-3-amine

The title compound was prepared in 98% yield from Preparation 13a according to the general procedure for Preparation 9b. [M+H] calc'd for C₁₈H₂₃N₃O, 298; found 298.

Example 13: 3-({[(1R)-6-[(6-methoxypyridin-3-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

3-Fluoroisonicotinic acid (52 mg, 0.36 mmol), Preparation 13b (108 mg, 0.36 mmol) and DIEA (64 μL, 0.36 mmol) were combined in DMA (2 mL), and the solution was heated at 168° C. in a microwave for 1 h. The solution was concentrated and purified by prep-HPLC (35-85% ACN/water with 0.1% formic acid) to give 58 mg (39%) of the title compound as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.61-1.80 (4H, m), 2.61-2.67 (2H, m), 2.99-3.04 (1H, m), 3.18 (3H, s), 3.40-3.55 (2H, m), 3.83 (3H, s), 6.54-6.60 (2H, m), 6.79 (1H, d, J=8.7 Hz), 7.15 (1H, d, J=8.5 Hz), 7.46 (1H, d, J=8.7 Hz), 7.55 (1H, d, J=5.0 Hz), 7.72 (1H, br s), 7.82 (1H, d, J=5.0 Hz), 7.95 (1H, s), 8.34 (1H, s), 13.29 (1H, br s). [M+H] calc'd for C₂₄H₂₆N₄O₃, 419; found 419.

Preparation 14a: (7-bromo-2H-chromen-4-yl)methanamine, Hydrochloride

To a solution of 7-bromochroman-4-one (5.00 g, 22.0 mmol) and ZnI₂ (30 mg) in toluene (50 mL) was added TMSCN (4.36 g, 44.0 mmol), and the mixture was heated at 60° C. overnight. The reaction mixture was cooled to rt, and a solution of LAH (20.0 mL, 2.4 M in THF, 44.0 mmol) was added slowly. The mixture was stirred at 40° C. for 2 h. The reaction was quenched with the addition of EtOAc (10 mL) at 0° C., followed by water (5 mL) and aqueous 10% NaOH (5 mL). The reaction mixture was diluted with EtOAc, dried (MgSO₄), filtered through Celite, and concentrated to give 4.5 g (79%) of the crude 4-(aminomethyl)-7-bromo-3,4-dihydro-2H-1-benzopyran-4-ol intermediate as a yellow oil.

To a solution of this intermediate (4.50 g, 17.4 mmol) in toluene (100 mL) was added 4N HCl/dioxane (20 mL) solution, and the mixture was stirred at reflux for 10 min. The mixture was cooled to rt and concentrated. The residue was precipitated from cold EtOAc and collected to give 3.6 g (75%) of the title compound as a yellow solid. [M+H] calc'd for C₁₀H₁₀BrNO, 240, 242; found 240, 242.

Preparation 14b: (7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl)methanamine

To a solution of Preparation 14a (2.0 g, 7.2 mmol) in MeOH (20 mL) and AcOH (2 mL) was added Raney Ni (200 mg) at rt. The suspension was stirred for overnight at under hydrogen at 50 psi. The reaction mixture was filtered, and the pH was adjusted to 7-8 with sat. Na₂CO₃. The solution was dried (Na₂SO₄) and concentrated to give 1.32 g (75%) of the title compound as a brown oil. [M+H] Calc'd for C₁₀H₁₂BrNO, 242, 244; Found, 242, 244.

Preparation 14c: methyl 3-{[(7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 44% yield from Preparation 9b according to the general procedure for Preparation 1e. [M+H] Calc'd for C₁₇H₁₇BrN₂O₃, 377, 379; Found, 377, 379.

Example 14: 3-{[(7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]amino}pyridine-4-carboxylic Acid

The title compound was prepared in 59% yield from Preparation 14c according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.87-2.01 (2H, m), 3.10-3.14 (1H, m), 3.49-3.55 (1H, m), 3.66-3.71 (1H, m), 4.16-4.23 (2H, m), 6.99-7.04 (2H, m), 7.27 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=4.8 Hz), 7.85 (1H, d, J=5.2 Hz), 8.42 (1H, s). [M+H] Calc'd for C₁₆H₁₅BrN₂O₃, 363, 365; Found, 363, 365.

Preparation 15a: methyl 3-({[7-(phenylamino)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

A suspension of Preparation 14c (100 mg, 0.26 mmol), aniline (25.0 mg, 0.26 mmol), Cs₂CO₃ (130 mg, 0.40 mmol), Pd(OAc)₂ (2.0 mg, 0.007 mmol) and BINAP (9.0 mg, 0.013 mmol) in toluene (10 mL) was stirred at 100° C. under N₂ overnight. The reaction was filtered and concentrated. Purification by silica gel chromatography (PE:EA=1:1) gave 54 mg (52%) of the title compound as a brown oil. [M+H] calc'd for C₂₃H₂₃N₃O₃, 390; found 390.

Example 15: 3-({[7-(phenylamino)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 71% yield from Preparation 15a according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.86-1.88 (1H, m), 1.96-1.99 (1H, m), 3.04-3.05 (1H, m), 3.3.43-3.48 (1H, m), 3.63-3.67 (1H, m), 4.12-4.17 (2H, m), 6.47 (1H, s), 6.48-6.61 (1H, m), 6.78-6.82 (1H, m), 7.04 (2H, d, J=8.0 Hz), 7.11-7.23 (3H, m), 7.58 (1H, d, J=4.8 Hz), 7.84 (1H, d, J=4.8 Hz), 8.08 (1H, s), 8.38 (1H, s). [M+H] calc'd for C₂₂H₂₁N₃O₃, 376; found 376.

Preparation 16a: tert-butyl [(7-bromo-2H-chromen-4-yl)methyl]carbamate

To a solution of Preparation 14a (3.6 g, 13 mmol) in DMF (30 mL) was added TEA (5.5 mL, 39 mmol) and (Boc)₂O (3.40 g, 15.6 mmol). The mixture was stirred at rt for 2 h. The reaction was concentrated and the residue was purified by silica gel chromatography (PE:EtOAc=4:1) to give 3.19 g (72%) of the title compound as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 6.97-7.03 (m, 3H), 5.72-5.75 (m, 1H), 4.76-4.79 (m, 2H), 4.67 (br s, 1H), 4.08-4.15 (m, 2H), 1.45 (s, 9H). [M+H] calc'd for C₁₅H₁₈BrNO₃, 340, 342; found 340, 342.

Preparation 16b: tert-butyl N-{[7-(1,2,3,4-tetrahydroquinolin-1-yl)-2H-chromen-4-yl]methyl}carbamate

To a solution of Preparation 16a (500 mg, 1.47 mmol) in THF (15 mL) was added 1,2,3,4-tetrahydroquinoline (215 mg, 1.62 mmol), Cs₂CO₃ (719 g, 2.21 mmol), BINAP (220 mg, 0.35 mmol) and Pd(OAc)₂ (40 mg, 0.18 mmol). The mixture was refluxed for overnight under nitrogen. The mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (PE:EtOAc=5:1) to give 360 mg (62%) of the title compound as a yellow oil. [M+H] calc'd for C₂₄H₂₈N₂O₃, 393; found 393.

Preparation 16c: [7-(1,2,3,4-tetrahydroquinolin-1-yl)-2H-chromen-4-yl]methanamine, Hydrochloride

A solution of Preparation 16b (360 mg, 0.918 mmol) in 4N HCl/EtOAc (20 mL) was stirred overnight at rt. The mixture was concentrated to give the crude title compound as a yellow solid. [M+H] calc'd for C₁₉H₂₀N₂O, 293; found 293.

Preparation 16d: [7-(1,2,3,4-tetrahydroquinolin-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

To a solution of Preparation 16c (300 mg, 0.913 mmol) in MeOH (20 mL) and conc. HCl (one drop) was added 10% Pd/C (30 mg) under N₂. The suspension was stirred at rt under 50 psi of hydrogen overnight. The reaction mixture was filtered, adjusted to pH=7˜8 with sat. K₂CO₃, dried (Na₂SO₄), and concentrated to give 240 mg (90%) of the title compound as a yellow oil. [M+H] calc'd for C₁₉H₂₂N₂O, 295; found 295.

Preparation 16e: methyl 3-({[7-(1,2,3,4-tetrahydroquinolin-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 16d (240 mg, 0.816 mmol) in toluene (10 mL) was added methyl 3-bromoisonicotinate (176 mg, 0.816 mmol), Pd₂(dba)₃ (15 mg, 0.016 mmol), Xantphos (29 mg, 0.049 mmol) and Cs₂CO₃ (373 mg, 1.14 mmol). The mixture was heated to reflux under nitrogen overnight. The mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (PE:EtOAc=2:1) to give 90 mg (26%) of the title compound as a yellow oil. [M+H] calc'd for C₂₆H₂₇N₃O₃, 430; found 430.

Example 16: 3-({[7-(1,2,3,4-tetrahydroquinolin-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 86% yield from Preparation 16f according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.87-2.02 (4H, m), 2.75 (2H, t, J=6.0 Hz), 3.08-3.12 (1H, m), 3.51-3.68 (3H, m), 3.68-3.72 (1H, m), 4.13-4.23 (2H, m), 6.58 (1H, s), 6.65 (2H, d, J=7.6 Hz), 6.70-6.73 (1H, m), 6.89 (1H, t, J=7.2 Hz), 7.00 (1H, d, J=7.2 Hz), 7.28 (1H, d, J=8.4 Hz), 7.58 (1H, d, J=4.8 Hz), 7.84 (1H, d, J=5.2 Hz), 8.41 (1H, s). [M+H] calc'd for C₂₅H₂₅N₃O₃, 416; found 416.

Preparation 17a: tert-butyl N-{[7-(2,3-dihydro-1H-indol-1-yl)-2H-chromen-4-yl]methyl}carbamate

The title compound was prepared in 59% yield from Preparation 16a and indoline according to the general procedure for Preparation 16c. [M+H] calc'd for C₂₃H₂₆N₂O₃, 379; found 379.

Preparation 17b: [7-(2,3-dihydro-1H-indol-1-yl)-2H-chromen-4-yl]methanamine, Hydrochloride

The title compound was prepared in 84% yield from Preparation 17a according to the general procedure for Preparation 16c. [M+H] calc'd for C₁₈H₁₈N₂O, 279; found 279.

Preparation 17c: [7-(2,3-dihydro-1H-indol-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 86% yield from Preparation 17b according to the general procedure for Preparation 16d. [M+H] calc'd for C₁₈H₂₀N₂O, 281; found 281.

Preparation 17d: methyl 3-({[7-(2,3-dihydro-1H-indol-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 17c (350 mg, 1.25 mmol) in DMA (6 mL) was added methyl 3-fluoroisonicotinate (195 mg, 1.25 mmol), and the reaction mixture was stirred at 170° C. for 1 h in a microwave. The reaction mixture was poured into water and extracted with EtOAc. Organics were washed with brine, dried (Na₂SO₄) and concentration. Purification by silica gel chromatography (PE:EtOAc=2:1) gave 79 mg (15%) of the title compound as a yellow gum. [M+H] calc'd for C₂₅H₂₅N₃O₃, 416; found 416.

Example 17: 3-({[7-(2,3-dihydro-1H-indol-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 43% yield from Preparation 17d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.87-1.90 (1H, m), 1.97-2.01 (1H, m), 3.03-3.09 (3H, m), 3.43-3.48 (1H, m), 3.63-3.68 (1H, m), 3.86 (2H, t, J=9.0 Hz), 4.13-4.21 (2H, m), 6.58 (1H, s), 6.67-6.71 (1H, m), 6.77-6.80 (1H, m), 7.02-7.05 (2H, m), 7.15 (1H, d, J=7.2 Hz), 7.26 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=4.8 Hz), 7.81 (1H, d, J=5.2 Hz), 8.35 (1H, s). [M+H] calc'd for C₂₄H₂₃N₃O₃, 402; found 402.

Preparation 18a: 7-bromo-2H-chromene-4-carboxamide

To a solution of 7-bromochroman-4-one (2.0 g, 8.8 mmol) and AlCl₃ (118 mg, 0.9 mmol) in toluene (10 mL) was added TMSCN (1.3 mL, 9.7 mmol). The solution was stirred at 40° C. for 1.5 h. The reaction was cooled to rt, and H₂SO₄ (1.0 mL) was added, followed by AcOH (13 mL) and more H₂SO₄ (4.3 mL). The reaction was heated to 130° C. and stirred for 6 h. The reaction was cooled, poured over H₂O (100 mL) and filtered. The filter cake dissolved in THF (50 mL) and filtered. The combined organic solutions were concentrated to give 1.0 g (45%) of the crude title compound as an off-white solid. [M+H] calc'd for C₁₀H₈BrNO₂, 254, 256; found 254, 256.

Preparation 18b: (4R)-7-bromo-3,4-dihydro-2H-1-benzopyran-4-carboxamide

To a solution of Preparation 18a (6.0 g, 23.6 mmol) in MeOH (70 mL) and THF (70 mL) was added Ru(OAc)₂[s-binap] (100 mg). The mixture was heated at 80° C. overnight with 5.0 MPa H₂. The solution was concentrated to get the crude title compound (ee>90%). This was re-crystallized from EtOAc to give 3.5 g (58%, ee>95%) as a white solid. [M+H] calc'd for C₁₀H₁₀BrNO₂, 256, 258; found 256, 258. Analytical Column: Chiralcel: AS-H, Mobile phase: CO₂:MeOH=70:30.

Preparation 18c: [(4R)-7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

To a solution of Preparation 18b (500 mg, 2.0 mmol) in THF (10 mL) was added BH₃.THF (9.8 mL, 1.0 M, 9.8 mmol) at rt. The mixture was heated at 45° C. for 3 h. The reaction was diluted with water (10 mL), basified to pH 9 with sat. Na₂CO₃, and then extracted with EtOAc (3×50 mL). Organics were washed with brine (50 mL), dried (Na₂SO₄), and concentrated to give 500 mg of the crude title compound as a yellow oil. [M+H] calc'd for C₁₀H₁₂BrNO, 242, 244; found 242, 244.

Preparation 18d: tert-butyl N-{[(4R)-7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

To a solution of Preparation 18c (2.0 mmol) and TEA (0.8 mL, 5.9 mmol) in DCM (10 mL) was added Boc₂O (510 mg, 2.3 mmol) at 0° C., and the reaction was stirred at rt overnight. The solution was concentrated and purified by silica gel chromatography (PE:EtOAc=10:1) to give 270 mg (41%) of the title compound as a yellow oil. [M+H] calc'd for C₁₅H₂₀BrNO₃, 342, 344; found 342, 344.

Preparation 18e: tert-butyl N-{[(4R)-7-[methyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 57% yield from Preparation 18d and N-methylaniline according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₂H₂₈N₂O₃, 369; found 369.

Preparation 18f: (4R)-4-(aminomethyl)-N-methyl-N-phenyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in quantitative yield from Preparation 18e according to the general procedure for Preparation 6f. [M+H] calc'd for C₁₇H₂₀N₂O, 269; found 269.

Preparation 18g: methyl 3-({[(4R)-7-[methyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 68% yield from Preparation 18f according to the general procedure for Preparation 16f. [M+H] calc'd for C₂₄H₂₅N₃O₃, 404; found 404.

Example 18: 3-({[(4R)-7-[methyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 32% yield from Preparation 18g according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.87-1.88 (1H, m), 1.96-1.97 (1H, m), 3.06-3.09 (1H, m), 3.20 (3H, s), 3.44-3.52 (1H, m), 3.64-3.66 (1H, m), 4.12-4.18 (2H, m), 6.36 (1H, d, J=2.1 Hz), 6.48 (1H, d, J=8.4 Hz), 6.91-7.01 (3H, m), 7.17-7.29 (3H, m), 7.56 (1H, d, J=5.1 Hz), 7.83 (1H, d, J=5.1 Hz), 8.40 (1H, s). [M+H] calc'd for C₂₃H₂₃N₃O₃, 390; found 390.

Preparation 19a: tert-butyl N-{[(4R)-7-[(2-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 65% yield from Preparation 18d and 2-fluoro-N-methylaniline according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₂H₂₇FN₂O₃, 387; found 387.

Preparation 19b: (4R)-4-(aminomethyl)-N-(2-fluorophenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in quantitative yield from Preparation 19a according to the general procedure for Preparation 6f. [M+H] calc'd for C₁₇H₁₉FN₂O, 287; found 287.

Preparation 19c: methyl 3-({[(4R)-7-[(2-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 50% yield from Preparation 19b according to the general procedure for Preparation 16e. [M+H] calc'd for C₂₄H₂₄FN₃O₃, 422; found 422.

Example 19: 3-({[(4R)-7-[(2-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 88% yield from Preparation 19c according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.81-1.85 (1H, m), 1.93-1.99 (1H, m), 2.99-3.02 (1H, m), 3.18 (3H, s), 3.41-3.44 (1H, m), 3.58-3.63 (1H, m), 4.08-4.14 (2H, m), 6.04 (1H, s), 6.18 (1H, dd, J=1.2, 7.2 Hz), 7.10 (1H, d, J=8.4 Hz), 7.24-7.34 (4H, m), 7.56 (1H, d, J=5.2 Hz), 7.82 (1H, d, J=4.8 Hz), 8.35 (1H, s). [M+H] calc'd for C₂₃H₂₂FN₃O₃, 408; found 408.

Preparation 20a: tert-butyl N-{[(4R)-7-[(3-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 83% yield from Preparation 18d and 3-fluoro-N-methylaniline according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₂H₂₇FN₂O₃, 387; found 387.

Preparation 20b: (4R)-4-(aminomethyl)-N-(3-fluorophenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in quantitative yield from Preparation 20a according to the general procedure for Preparation 6f. [M+H] calc'd for C₁₇H₁₉FN₂O, 287; found 287.

Preparation 20c: methyl 3-({[(4R)-7-[(3-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 12% yield from Preparation 20b according to the general procedure for Preparation 16e. [M+H] calc'd for C₂₄H₂₄FN₃O₃, 422; found 422.

Example 20: 3-({[(4R)-7-[(3-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 46% yield from Preparation 20c according to the general procedure for Example 1. ¹H NMR (400 MHz, THF-d₈): δ 8.30 (s, 1H), 7.74 (brs, 2H), 7.48 (d, J=4.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.03-6.97 (m, 1H), 6.59-6.45 (m, 4H), 6.36 (t, J=8.0 Hz, 1H), 4.13-4.02 (m, 2H), 3.65-3.59 (m, 1H), 3.42-3.34 (m, 1H), 3.14 (s, 3H), 3.08-3.02 (m, 1H), 2.00-1.86 (m, 2H). [M+H] calc'd for C₂₃H₂₂FN₃O₃, 408; found 408.

Preparation 21a: tert-butyl N-{[(4R)-7-[(4-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 55% yield from Preparation 18d and 4-fluoro-N-methylaniline according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₂H₂₇FN₂O₃, 387; found 387.

Preparation 21b: (4R)-4-(aminomethyl)-N-(4-fluorophenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in quantitative yield from Preparation 21a according to the general procedure for Preparation 6f. [M+H] calc'd for C₁₇H₁₉FN₂O, 287; found 287.

Preparation 21c: methyl 3-({[(4R)-7-[(4-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 83% yield from Preparation 21b according to the general procedure for Preparation 16e. [M+H] calc'd for C₂₄H₂₄FN₃O₃, 422; found 422.

Example 21: 3-({[(4R)-7-[(4-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 83% yield from Preparation 21c according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.82-1.87 (1H, m), 1.94-1.99 (1H, m), 3.03-3.06 (1H, m), 3.17 (3H, s), 3.43-3.49 (1H, m), 3.63-3.67 (1H, m), 4.09-4.20 (2H, m), 6.26 (1H, s), 6.38 (1H, d, J=8.4 Hz), 7.04-7.08 (2H, m), 7.11-7.16 (3H, m), 7.56 (1H, d, J=5.2 Hz), 7.83 (1H, d, J=4.8 Hz), 8.39 (1H, s). [M+H] calc'd for C₂₃H₂₂FN₃O₃, 408; found 408.

Preparation 22a: tert-butyl N-{[(4R)-7-[methyl(4-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 45% yield from Preparation 18d and 4-methyl-N-methylaniline according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₃H₃₀N₂O₃, 383; found 383.

Preparation 22b: (4R)-4-(aminomethyl)-N-methyl-N-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in quantitative yield from Preparation 22a according to the general procedure for Preparation 6f. [M+H] calc'd for C₁₈H₂₂N₂O, 283; found 283.

Preparation 22c: methyl 3-({[(4R)-7-[methyl(4-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 29% yield from Preparation 22b according to the general procedure for Preparation 16e. [M+H] calc'd for C₂₅H₂₇N₃O₃, 418; found 418.

Example 22: 3-({[(4R)-7-[methyl(4-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 79% yield from Preparation 22c according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.84-1.86 (1H, m), 1.95-1.99 (1H, m), 2.26 (3H, s), 3.02-3.05 (1H, m), 3.16 (3H, s), 3.42-3.48 (1H, m), 3.62-3.66 (1H, m), 4.08-4.16 (2H, m), 6.25 (1H, s), 6.38-6.40 (1H, m), 6.95 (2H, d, J=8.0 Hz), 7.10-7.14 (3H, m), 7.56 (1H, d, J=5.2 Hz), 7.84 (1H, d, J=5.2 Hz), 8.38 (1H, s). [M+H] calc'd for C₂₄H₂₅N₃O₃, 404; found 404.

Preparation 23a: tert-butyl N-{[(4R)-7-[(4-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 65% yield from Preparation 18d and 4-chloro-N-methylaniline according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₂H₂₇ClN₂O₃, 403; found 403.

Preparation 23b: (4R)-4-(aminomethyl)-N-(4-chlorophenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in quantitative yield from Preparation 23a according to the general procedure for Preparation 6f. [M+H] calc'd for C₁₇H₁₉ClN₂O, 303; found 303.

Preparation 23c: methyl 3-({[(4R)-7-[(4-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 18% yield from Preparation 21b according to the general procedure for Preparation 16e. [M+H] calc'd for C₂₄H₂₄ClN₃O₃, 438; found 438.

Example 23: 3-({[(4R)-7-[(4-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 51% yield from Preparation 23c according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 8.39 (s, 1H), 7.84 (d, J=4.8 Hz, 1H), 7.56 (d, J=4.8 Hz, 1H), 7.27-7.23 (m, 3H), 6.92 (d, J=8.8 Hz, 2H), 6.56 (dd, J=8.0 Hz, 2.0 Hz, 1H), 6.45 (d, J=2.0 Hz, 1H), 4.23-4.12 (m, 2H), 3.71-3.66 (m, 1H), 3.52-3.46 (m, 1H), 3.20 (s, 3H), 3.11-3.07 (m, 1H), 2.02-1.95 (m, 1H), 1.89-1.86 (m, 1H). [M+H] calc'd for C₂₃H₂₂ClN₃O₃, 424; found 424.

Preparation 24a: tert-butyl N-{[(4R)-7-[ethyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 68% yield from Preparation 18d and N-ethylaniline according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₃H₃₀N₂O₃, 383; found 383.

Preparation 24b: (4R)-4-(aminomethyl)-N-ethyl-N-phenyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in quantitative yield from Preparation 24a according to the general procedure for Preparation 6f. [M+H] calc'd for C₁₈H₂₂N₂O, 283; found 283.

Preparation 24c: methyl 3-({[(4R)-7-[ethyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 33% yield from Preparation 22b according to the general procedure for Preparation 16e. [M+H] calc'd for C₂₅H₂₇N₃O₃, 418; found 418.

Example 24: 3-({[(4R)-7-[ethyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 58% yield from Preparation 24c according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.10 (3H, t, J=6.8 Hz), 1.83-1.87 (1H, m), 1.95-2.00 (1H, m), 3.05-3.08 (1H, m), 3.45-3.51 (1H, m), 3.65-3.72 (3H, m), 4.10-4.18 (2H, m), 6.33 (1H, s), 6.4 (1H, d, J=8.0 Hz), 6.91-6.98 (3H, m), 7.17 (1H, d, J=8.4 Hz), 7.26 (2H, t, J=7.6 Hz), 7.57 (1H, d, J=4.4 Hz), 7.84 (1H, d, J=4.8 Hz), 8.40 (1H, s). [M+H] calc'd for C₂₄H₂₅N₃O₃, 404; found 404.

Preparation 25a: 2-hydroxy-5,6,7,8-tetrahydroquinolin-5-one

A mixture of 3-amino-2-cyclohexen-1-one (25.0 g, 224.9 mmol) and methyl propiolate (23.6 g, 281 mmol) was heated to reflux for 1 h. The mixture was cooled and the solid was collected by filtration, washing with THF, to give 7.8 g (21%) of the title compound as a yellow solid. [M+H] calc'd for C₉H₉NO₂, 164; found 164.

Preparation 25b: 2-chloro-5,6,7,8-tetrahydroquinolin-5-one

To the suspension of Preparation 25a (7.8 g, 47.7 mmol) in ACN (120 mL) was added POCl₃ (14.6 g, 95.3 mmol) dropwise. The reaction mixture was heated to reflux for 2 h and then concentrated. The residue was dissolved in H₂O, basified to pH 8 with 2N NaOH, and extracted with EtOAc. Organics were concentrated and purified by silica gel chromatography (PE:EtOAc=4:1) to give 7.1 g (82%) of the title compound as an off-white solid. [M+H] calc'd for C₉H₈ClNO, 182; found 182.

Preparation 25c: 2-phenyl-5,6,7,8-tetrahydroquinolin-5-one

The suspension of Preparation 25b (0.82 g, 4.5 mmol), phenylboronic acid (1.1 g, 9.1 mmol), Pd(Ph₃P)₄ (0.25 g, 0.23 mmol), and Na₂CO₃ (1.5 g, 13.6 mmol) in dioxane (30 mL) and H₂O (2 mL) was heated to reflux overnight under N₂. The reaction mixture was cooled, filtered, and concentrated. Purification by silica gel chromatography (PE:EtOAc=9:1) gave 1.1 g (85%) of the title compound as a white solid. [M+H] calc'd for C₁₅H₁₃NO₂, 224; found 224.

Preparation 25d: (2-phenyl-7,8-dihydroquinolin-5-yl)methanamine, H₂SO₄ Salt

To a solution of Preparation 25c (1.0 g, 4.6 mmol) and ZnI₂ (20 mg) in toluene (20 mL) was added TMSCN (0.91 g, 9.2 mmol) at rt. The solution was heated at 110° C. overnight. The reaction was cooled to 0° C., and LAH (3.9 mL, 2.4 M, 9.2 mmol) was added, and the reaction stirred for 2 h. The reaction was quenched with addition of EtOAc (20 mL) at 0° C., followed by water (0.4 mL) and aqueous 10% NaOH (0.4 mL). The mixture was filtered and concentrated. The resulting solid was washed with MTBE to give 0.55 g (47%) of the 5-(aminomethyl)-2-phenyl-5,6,7,8-tetrahydroquinolin-5-ol intermediated as a brown solid. To a solution of 5-(aminomethyl)-2-phenyl-5,6,7,8-tetrahydroquinolin-5-ol (0.55 g, 2.2 mmol) in toluene (80 mL) was added conc. H₂SO₄ (24 drops), and the solution was stirred at 150° C. under a Dean-Stark condenser. The solution was cooled to rt and concentrated to give the crude title compound. [M+H] calc'd for C₁₆H₁₆N₂, 237; found 237.

Preparation 25e: (2-phenyl-5,6,7,8-tetrahydroquinolin-5-yl)methanamine

To a solution of Preparation 25d (2.2 mmol) in MeOH (20 mL) and AcOH (2 mL) under N₂ was added 10% Pd/C (270 mg) at rt. The mixture was heated to 50° C. overnight under H₂. The reaction was filtered through Celite and concentrated. The residue was diluted with EtOAc, washed with sat. K₂CO₃ solution, dried (Na₂SO₄), and concentrated to 0.52 g of the crude title compound as a brown oil. [M+H] calc'd for C₁₆H₁₈N₂, 239; found 239.

Preparation 25f: methyl 3-({[(4R)-7-[ethyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 54% yield from Preparation 25e according to the general procedure for Preparation 4d. [M+H] Calc'd for C₂₃H₂₃N₃O₂, 374; Found, 374.

Example 25: 3-({[(4R)-7-[ethyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 41% yield from Preparation 25f according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.79-2.00 (m, 4H), 2.88-2.94 (m, 2H), 3.22-3.23 (m, 1H), 3.50-3.56 (m, 1H), 3.64-3.68 (m, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.47 (t, J=7.6 Hz, 2H), 7.57 (d, J=4.8 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.85 (d, J=4.8 Hz, 1H), 8.05 (d, J=7.6 Hz, 2H), 8.43 (s, 1H). [M+H] Calc'd for C₂₂H₂₁N₃O₂, 360; Found, 360.

Preparation 26a: 2-[methyl(phenyl)amino]-5,6,7,8-tetrahydroquinolin-5-one

To a solution of Preparation 25b (4.5 g, 24.7 mmol) in toluene (100 mL) was added N-methylaniline (5.3 g, 49.4 mmol), Pd₂(dba)₃ (456 mg, 0.49 mmol), Xantphos (0.86 g, 1.48 mmol) and Cs₂CO₃ (11.3 g, 34.6 mmol). The mixture was heated to reflux under nitrogen overnight. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=20:1 to 10:1) to give 1.6 g (26%) of the title compound as an off-white solid. [M+H] calc'd for C₁₆H₁₆N₂O, 253; found 253.

Preparation 26b: 5-(aminomethyl)-N-methyl-N-phenyl-7,8-dihydroquinolin-2-amine, Hydrochloride

The title compound was prepared in 51% yield from Preparation 26a according to the general procedure for Preparation 25d. [M+H] calc'd for C₁₇H₁₉N₂, 266; found 266.

Preparation 26c: 5-(aminomethyl)-N-methyl-N-phenyl-5,6,7,8-tetrahydroquinolin-2-amine

The title compound was prepared in quantitative yield from Preparation 26b according to the general procedure for Preparation 25e. [M+H] calc'd for C₁₇H₂₁N₂, 268; found 268.

Preparation 26d: methyl 3-[({2-[methyl(phenyl)amino]-5,6,7,8-tetrahydroquinolin-5-yl}methyl)amino]pyridine-4-carboxylate

The title compound was prepared in 30% yield from Preparation 26c according to the general procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₆N₄O₂, 403; Found, 403.

Example 26: 3-[({2-[methyl(phenyl)amino]-5,6,7,8-tetrahydroquinolin-5-yl}methyl)amino]pyridine-4-carboxylic Acid

The title compound was prepared in 47% yield from Preparation 26d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.72-1.93 (m, 4H), 2.67-2.73 (m, 2H), 2.98-3.02 (m, 1H), 3.37 (s, 3H), 3.40-3.43 (m, 1H), 3.50-3.54 (m, 1H), 6.35 (d, J=8.4 Hz, 1H), 7.18 (t, J=7.2 Hz, 1H), 7.25 (d, J=7.2 Hz, 2H), 7.39 (d, J=7.2 Hz, 2H), 7.41 (d, J=8.4 Hz, 1H), 7.55 (d, J=4.8 Hz, 1H), 7.82 (d, J=4.8 Hz, 1H), 8.34 (s, 1H). [M+H] Calc'd for C₂₃H₂₄N₄O₂, 389; Found, 389.

Preparation 27a: 7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-one

To a solution of 7-bromo-4-chromanone (1.0 g, 4.4 mmol) in DMF (15 mL) was added [4-(trifluoromethyl)phenyl]boronic acid (1.25 g, 6.6 mmol), Pd(PPh₃)₄ (580 mg, 0.5 mmol) and K₂CO₃ (1.22 g, 8.8 mmol). The mixture was stirred at 105° C. for 4 h under nitrogen. The mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (PE:EtOAc=4:1) to give 830 mg (61%) of the title compound as white solid. [M+H] Calc'd for C₁₆H₁₁F₃O₂, 293; Found, 293.

Preparation 27b: {7-[4-(trifluoromethyl)phenyl]-2H-chromen-4-yl}methanamine, Hydrochloride

The title compound was prepared in 41% yield from Preparation 27a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₇H₁₄F₃NO, 306; Found, 306.

Preparation 27c: {7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methanamine

The title compound was prepared in 80% yield from Preparation 27b according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₇H₁₆F₃NO, 308; Found, 308.

Preparation 27d: methyl 3-[({7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)amino]pyridine-4-carboxylate

To a solution of Preparation 27c (260 mg, 0.85 mmol) in DMA (10 mL) was added methyl 3-fluoroisonicotinate (330 mg, 2.2 mmol) at rt. The reaction mixture was stirred at 170° C. for 1 h in a microwave. The reaction mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated. Purification by silica gel chromatography gave 28 mg (7%) of the title compound as yellow solid. [M+H] Calc'd for C₂₄H₂₁F₃N₂O₃, 443; Found, 443.

Example 27: 3-[({7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)amino]pyridine-4-carboxylic Acid

The title compound was prepared in 59% yield from Preparation 38a according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.94-1.96 (1H, m), 2.02-2.03 (1H, m), 3.17-3.22 (1H, m), 3.50-3.56 (1H, m), 3.71-3.74 (1H, m), 4.21-4.27 (2H, m), 7.14 (1H, s), 7.23 (1H, d, J=7.2 Hz), 7.45 (1H, d, J=8.4 Hz), 7.58 (1H, d, J=4.8 Hz), 7.77-7.87 (5H, m), 8.41 (1H, s). [M+H] Calc'd for C₂₃H₁₉F₃N₂O₃, 429; Found, 429.

Preparation 28a: 7-(furan-3-yl)-3,4-dihydro-2H-1-benzopyran-4-one

To a solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (1.5 g, 6.6 mmol) in dioxane (6 mL) was added 2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.92 g, 9.9 mmol), Pd(dppf)Cl₂.DCM (540 mg, 0.66 mmol) and sat. NaHCO₃ (2 mL). The mixture was stirred at 100° C. for 4 h under nitrogen. The mixture was cooled to rt and diluted with EtOAc, filtered, and concentrated. The residue was purified by silica gel chromatography (4:1 PE:EtOAc) to give 1.18 g (83%) of the title compound as white solid. ¹H NMR (400 MHz, CDCl₃): δ 2.82 (2H, t, J=6.2 Hz), 4.56 (2H, t, J=6.4 Hz), 6.71 (1H, s), 7.07 (1H, s), 7.14 (1H, d, J=8.4 Hz), 7.50 (1H, s), 7.81 (1H, s), 7.88 (1H, d, J=8.4 Hz). [M+H] Calc'd for C₁₃H₁₀O₃, 215; Found, 215.

Preparation 28b: [7-(furan-3-yl)-2H-chromen-4-yl]methanamine, Hydrochloride

The title compound was prepared in 87% yield from Preparation 28a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₄H₁₃NO₂, 228; Found, 228.

Preparation 28c: [7-(furan-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 57% yield from Preparation 28b according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₄H₁₅NO₂, 230; Found, 230.

Preparation 28d: methyl 3-({[7-(furan-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 14% yield from Preparation 28c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₁H₂₀N₂O₄, 365; Found, 365.

Example 28: 3-({[7-(furan-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 71% yield from Preparation 28d according to the general procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.89-1.91 (1H, m), 1.97-2.00 (1H, m), 3.11-3.16 (1H, m), 3.48-3.56 (1H, m), 3.67-3.72 (1H, m), 4.17-4.23 (2H, m), 6.92 (1H, s), 7.03 (1H, s), 7.10 (1H, d, J=8.1 Hz), 7.29 (1H, d, J=8.1 Hz), 7.56 (1H, d, J=5.1 Hz), 7.70 (1H, s), 7.84 (1H, d, J=5.1 Hz), 8.14 (1H, s), 8.43 (1H, s). [M+H] Calc'd for C₂₀H₁₈N₂O₄, 351; Found, 351.

Preparation 29a: 7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-one

To a suspension of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (2.0 g, 8.9 mmol), 3-methylbenzeneboronic acid (1.8 g, 13.2 mmol), Na₂CO₃ (2.8 g, 26.4 mmol) in dioxane (40 mL) and water (2 mL) was added Pd(PPh₃)₄ (509 mg, 0.4 mmol) at rt under N₂. The reaction was stirred at 100° C. overnight. The reaction was filtered and concentrated. Purification by silica gel chromatography (PE:EtOAc=12:1) gave 2.0 g (96%) of the title compound as a white oil. ¹H NMR (300 MHz, CDCl₃): δ 2.44 (3H, s), 2.86 (2H, t, J=6.6 Hz), 4.59 (2H, t, J=6.6 Hz), 7.20-7.29 (3H, m), 7.36-7.44 (3H, m), 7.87 (1H, d, J=8.1 Hz). [M+H] Calc'd for C₁₆H₁₄O₂, 239; Found, 239.

Preparation 29b: [7-(3-methylphenyl)-2H-chromen-4-yl]methanamine

The title compound was prepared in 29% yield from Preparation 29a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₇H₁₇NO, 252; Found, 252.

Preparation 29c: [7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 99% yield from Preparation 29b according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₇H₁₉NO, 254; Found, 254.

Preparation 29d: methyl 3-({[(4S)-7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 30d: methyl 3-({[(4R)-7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds (200 mg) was prepared in 22% yield from Preparation 29c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₄H₂₄N₂O₃, 389; Found, 389.

Separation by chiral HPLC (Column: Chiralcel IA Sum 4.6*250 mm, Mobile phase: Hex:EtOH=50:50; F: 1.0 mL/min; W: 230 nm; T: 30° C.) gave 50 mg (25%) of Preparation 30d (9.211 min) and 52 mg (26%) of Preparation 29d (11.640 min), each as a yellow oil.

Example 29: 3-({[(4S)-7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 89% yield from Preparation 29d according to the general procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.90-1.94 (1H, m), 2.00-2.04 (1H, m), 2.36 (3H, s), 3.17-3.20 (1H, m), 3.51-3.58 (1H, m), 3.71-3.77 (1H, m), 4.21-4.25 (2H, m), 7.03 (1H, d, J=0.9 Hz), 7.13-7.16 (2H, m), 7.29-7.43 (4H, m), 7.58 (1H, d, J=5.1 Hz), 7.86 (1H, d, J=5.1 Hz), 8.45 (1H, s). [M+H] Calc'd for C₂₃H₂₂N₂O₃, 375; Found, 375.

Example 30: 3-({[(4R)-7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 90% yield from Preparation 30d according to the general procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.90-1.94 (1H, m), 2.00-2.04 (1H, m), 2.36 (3H, s), 3.17-3.20 (1H, m), 3.51-3.58 (1H, m), 3.71-3.77 (1H, m), 4.21-4.25 (2H, m), 7.03 (1H, d, J=0.9 Hz), 7.13-7.16 (2H, m), 7.29-7.43 (4H, m), 7.58 (1H, d, J=5.1 Hz), 7.86 (1H, d, J=5.1 Hz), 8.45 (1H, s). [M+H] Calc'd for C₂₃H₂₂N₂O₃, 375; Found, 375.

Preparation 31a: 7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-one

The title compound was prepared in 95% yield from 4-methylbenzeneboronic acid according to the general procedure for Preparation 27a. ¹H NMR (400 MHz, CDCl₃): δ 2.40 (3H, s), 2.82 (2H, t, J=6.6 Hz), 4.56 (2H, t, J=6.4 Hz), 7.17 (1H, s), 7.23-7.27 (3H, m), 7.49 (2H, d, J=8.0 Hz), 7.92 (1H, d, J=8.4 Hz). [M+H] Calc'd for C₁₆H₁₄O₂, 239; Found, 239.

Preparation 31b: [7-(4-methylphenyl)-2H-chromen-4-yl]methanamine, Hydrochloride

The title compound was prepared in 51% yield from Preparation 31a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₇H₁₇NO, 252; Found, 252.

Preparation 31c: [7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 72% yield from Preparation 31b according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₇H₁₉NO, 254; Found, 254.

Preparation 31d: methyl 3-({[(4S)-7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 32d: methyl 3-({[(4R)-7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds (370 mg) was prepared in 30% yield from Preparation 29c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₄H₂₄N₂O₃, 389; Found, 389.

Separation by chiral HPLC (Column: Chiralcel IA, 250 mm*4.6 mm, Sum; Mobile phase: Hex:EtOH=50:50; F: 1.0 mL/min; W: 230 nm; T=30° C.) give 160 mg (43%) of Preparation 32d (10.07 min) and 135 mg (36%) of Preparation 31d (12.88 min), each as a yellow oil.

Example 31: 3-({[(4S)-7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 59% yield from Preparation 31d according to the general procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.90-1.92 (1H, m), 1.99-2.04 (1H, m), 2.32 (3H, s), 3.20-3.25 (1H, m), 3.59-3.64 (1H, m), 3.73-3.77 (1H, m), 4.16-4.25 (2H, m), 7.03 (1H, s), 7.11 (1H, d, J=7.5 Hz), 7.22 (2H, d, J=7.5 Hz), 7.37 (1H, d, J=7.8 Hz), 7.49 (2H, d, J=7.8 Hz), 8.03 (1H, d, J=5.7 Hz), 8.13 (1H, d, J=5.4 Hz), 8.30 (1H, bs), 8.61 (1H, s).

[M+H] Calc'd for C₂₃H₂₂N₂O₃, 375; Found, 375.

Example 32: 3-({[(4R)-7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 71% yield from Preparation 32d according to the general procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.90-1.92 (1H, m), 1.99-2.04 (1H, m), 2.32 (3H, s), 3.20-3.25 (1H, m), 3.59-3.64 (1H, m), 3.73-3.77 (1H, m), 4.16-4.25 (2H, m), 7.02 (1H, s), 7.11 (1H, d, J=8.1 Hz), 7.21 (2H, d, J=8.1 Hz), 7.36 (1H, d, J=8.4 Hz), 7.48 (2H, d, J=7.8 Hz), 8.03 (1H, d, J=5.7 Hz), 8.14 (1H, d, J=5.7 Hz), 8.30 (1H, bs), 8.61 (1H, s). [M+H] Calc'd for C₂₃H₂₂N₂O₃, 375; Found, 375.

Preparation 33a: 7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-one

The title compound was prepared in 85% yield from 3-thienylboronic acid according to the general procedure for Preparation 27a. [M+H] Calc'd for C₁₃H₁₀O₂S, 231; Found, 231.

Preparation 33b: [7-(thiophen-3-yl)-2H-chromen-4-yl]methanamine, Hydrochloride

The title compound was prepared in 77% yield from Preparation 33a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₄H₁₃NOS, 244; Found, 244.

Preparation 33c: [7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 99% yield from Preparation 33b according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₄H₁₅NOS, 246; Found, 246.

Preparation 33d: methyl 3-({[(4S)-7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 34d: methyl 3-({[(4R)-7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds (250 mg) was prepared in 16% yield from Preparation 33c according to the general procedure for Preparation 1e.

Separation by chiral HPLC (Column: Chiralcel: AS 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=80:20, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 83 mg (33%) of Preparation 34d (9.489 min) and 76 mg (30%) of Preparation 33d (11.968 min), each as a yellow solid.

Example 33: 3-({[(4S)-7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 64% yield from Preparation 33d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.90-1.92 (1H, m), 1.99-2.03 (1H, m), 3.14-3.18 (1H, m), 3.52-3.58 (1H, m), 3.71-3.75 (1H, m), 4.19-4.25 (2H, m), 7.14 (1H, s), 7.22 (1H, d, J=8.0 Hz), 7.34 (1H, d, J=8.0 Hz), 7.52-7.62 (3H, m), 7.85-7.87 (2H, m), 8.45 (1H, s). [M+H] Calc'd for C₂₀H₁₈N₂O₃S, 367; Found, 367.

Example 34: 3-({[(4R)-7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 62% yield from Preparation 34d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.92-1.93 (1H, m), 1.99-2.03 (1H, m), 3.16-3.17 (1H, m), 3.55-3.57 (1H, m), 3.71-3.75 (1H, m), 4.20-4.24 (2H, m), 7.13 (1H, s), 7.22 (1H, d, J=8.4 Hz), 7.34 (1H, d, J=8.0 Hz), 7.52-7.61 (3H, m), 7.85-7.86 (2H, m), 8.44 (1H, s). [M+H] Calc'd for C₂₀H₁₈N₂O₃S, 367; Found, 367.

Preparation 35a: tert-butyl N-{[7-(cyclohex-1-en-1-yl)-2H-chromen-4-yl]methyl}carbamate

To a solution of Preparation 3b (600 mg, 1.76 mmol) in dioxane (25 mL) was added compound 1-cyclohexen-yl-boronic acid pinacol ester (404 mg, 1.94 mmol), Pd(PPh₃)₄ (204 mg, 1.76 mmol), Na₂CO₃ (8.0 mL, 2.0 mol/L, 14 mmol). The mixture was stirred at 80° C. for overnight under nitrogen. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=5:1) to give 450 mg (75%) of the title compound as a light red solid. [M+H] Calc'd for C₂₁H₂₇NO₃, 342; Found, 342.

Preparation 35b: tert-butyl N-[(7-cyclohexyl-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]carbamate

The title compound was prepared in 88% yield from Preparation 35a according to the general procedure for Preparation 3e. [M+H] Calc'd for C₂₁H₃₁NO₃, 346; Found, 346.

Preparation 35c: (7-cyclohexyl-3,4-dihydro-2H-1-benzopyran-4-yl)methanamine

To a solution of Preparation 35b (400 mg, 1.16 mmol) in EtOAc (10 mL) was added EtOAc/HCl (10 mL, 1.0 M), and the reaction mixture was stirred at rt for 4 h. The reaction mixture was concentrated, and the residue was taken up in sat. aq. K₂CO₃ (20 mL) and extracted with EtOAc (3×10 mL). Organics were dried (Na₂SO₄) and concentrated to give 289 mg (quantitative) of the title compound as a pale brown oil. [M+H] Calc'd for C₁₆H₂₃NO, 246; Found, 246.

Preparation 35d: methyl 3-({[(4R)-7-cyclohexyl-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 20% yield from Preparation 35c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₃H₂₈N₂O₃, 381; Found, 381.

Example 35: 3-({[(4R)-7-cyclohexyl-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 48% yield from Preparation 35d according to the general procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.31-1.37 (5H, m), 1.66-1.97 (7H, m), 2.36-2.39 (1H, m), 3.06-3.08 (1H, m), 3.46-3.48 (1H, m), 3.64-3.69 (1H, m), 4.14-4.17 (2H, m), 6.60 (1H, s), 6.71 (1H, d, J=7.2 Hz), 7.20 (1H, d, J=8.1 Hz), 7.57 (1H, d, J=4.8 Hz), 7.85 (1H, d, J=4.8 Hz), 8.41 (1H, s). [M+H] Calc'd for C₂₂H₂₆N₂O₃, 367; Found, 367.

Preparation 36a: methyl 3-({[7-(2-methylthiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 14c (285 mg, 0.756 mmol) in DME (15 mL) was added compound 2-methylthiophene-3-boronic acid (161 mg, 1.13 mmol), Pd(PPh₃)₄ (88 mg, 0.76 mmol) and Na₂CO₃ (1.2 mL, 2 N, 2.4 mmol). The mixture was stirred at reflux overnight under nitrogen. The mixture was diluted with EtOAc, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=1:1) to give 117 mg (39%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₂H₂₂N₂O₃S, 395; Found, 395.

Preparation 36b: methyl 3-({[(4S)-7-(2-methylthiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 37b: methyl 3-({[(4R)-7-(2-methylthiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

Preparation 36a (117 mg) was separated by chiral HPLC (Column: Chiralcel OD, 250 mm*4.6 mm 5 um; Mobile phase: Hex:EtOH:DEA=70:30:0.2; F: 1.0 mL/min; W: 230 nm; T=30° C.) gave 47 mg (31%) of Preparation 36b (8.686 min) and 44 mg (29%) of Preparation 37b (10.759 min), each as a yellow oil.

Example 36: 3-({[(4S)-7-(2-methylthiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 91% yield from Preparation 36b according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.89-1.93 (1H, m), 2.00-2.05 (1H, m), 2.46 (3H, s), 3.19-3.22 (1H, m), 3.57-3.62 (1H, m), 3.76-3.80 (1H, m), 4.17-4.28 (2H, m), 6.82 (1H, s), 6.91-6.93 (1H, m), 7.07 (1H, d, J=5.2 Hz), 7.32-7.39 (2H, m), 7.92-7.96 (2H, m), 8.07-8.09 (1H, m), 8.56 (1H, s). [M+H] Calc'd for C₂₁H₂₀N₂O₃S, 381; Found, 381.

Example 37: 3-({[(4R)-7-(2-methylthiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 95% yield from Preparation 37b according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.90-1.93 (1H, m), 2.01-2.04 (1H, m), 2.46 (3H, s), 3.16-3.21 (1H, m), 3.51-3.59 (1H, m), 3.72-3.77 (1H, m), 4.19-4.25 (2H, m), 6.82 (1H, s), 6.91-6.93 (1H, m), 7.07 (1H, d, J=5.2 Hz), 7.32-7.38 (2H, m), 7.65 (1H, d, J=5.2 Hz), 7.88 (1H, d, J=5.2 Hz), 8.47 (1H, s). [M+H] Calc'd for C₂₁H₂₀N₂O₃S, 381; Found, 381.

Preparation 38a: methyl 3-({[7-(3-methylbut-1-yn-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

To a suspension of Preparation 14c (50 mg, 0.13 mmol), 3-methyl-1-butyne (27 mg, 0.40 mmol), PPh₃ (17 mg, 0.065 mmol) and CuI (5 mg, 0.026 mmol) in TEA (10 mL) was added Pd₂(dba)₃ (12 mg, 0.013 mmol) at rt under N₂. The reaction was stirred at reflux overnight. The reaction was concentrated and purified by prep-HPLC to give 25 mg (52%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₂H₂₄N₂O₃, 365; Found, 365.

Example 38: 3-({[7-(3-methylbut-1-yn-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 83% yield from Preparation 38a according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.19-1.26 (6H, m), 1.87-1.99 (2H, m), 2.75-2.82 (1H, m), 3.12-3.15 (1H, m), 3.48-3.54 (1H, m), 3.66-3.71 (1H, m), 4.15-4.21 (2H, m), 6.73 (1H, d, J=1.2 Hz), 6.84 (1H, dd, J=1.2, 8.0 Hz), 7.26 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=4.4 Hz), 7.84 (1H, d, J=4.4 Hz), 8.41 (1H, s). [M+H] Calc'd for C₂₁H₂₂N₂O₃, 351; Found, 351.

Preparation 39a: methyl 3-({[(4S)-7-(2-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 40a: methyl 3-({[(4R)-7-(2-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 14c (300 mg, 0.8 mmol) in DMF (10 mL) was added 2-chlorophenylboronic acid (186 mg, 1.2 mmol), Pd(PPh₃)₄ (92 mg, 0.08 mmol) and K₂CO₃ (221 mg, 1.6 mmol). The mixture was stirred at 105° C. for 12 h under nitrogen. The mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (PE:EtOAc=2:1) to give 150 mg (46%) of the racemate as colorless oil. [M+H] Calc'd for C₂₃H₂₁ClN₂O₃, 409; Found, 409.

Separation by chiral HPLC (Column: Chiralcel: IA 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 40 mg (27%) of Preparation 40a (8.862 min) and 45 mg (30%) of Preparation 39a (11.567 min), each as a yellow oil.

Example 39: 3-({[(4S)-7-(2-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 90% yield from Preparation 39a according to the general procedure for Example 1. ¹H NMR (400 MHz, CD₃OD): δ 1.92-1.97 (1H, m), 2.08-2.12 (1H, m), 3.18-3.21 (1H, m), 3.51-3.56 (1H, m), 3.67-3.72 (1H, m), 4.14-4.23 (2H, m), 6.73 (1H, s), 6.79 (1H, d, J=9.2 Hz), 7.19-7.25 (4H, m), 7.37 (1H, d, J=9.6 Hz), 7.13 (1H, d, J=2.0 Hz), 8.12 (1H, d, J=4.0 Hz), 8.29 (1H, s). [M+H] Calc'd for C₂₂H₁₉ClN₂O₃, 395; Found, 395.

Example 40: 3-({[(4R)-7-(2-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 81% yield from Preparation 40a according to the general procedure for Example 1. ¹H NMR (400 MHz, CD₃OD): δ 1.92-1.97 (1H, m), 2.08-2.12 (1H, m), 3.18-3.21 (1H, m), 3.51-3.56 (1H, m), 3.67-3.72 (1H, m), 4.14-4.23 (2H, m), 6.73 (1H, s), 6.79 (1H, d, J=9.2 Hz), 7.19-7.25 (4H, m), 7.37 (1H, d, J=9.6 Hz), 7.13 (1H, d, J=2.0 Hz), 8.12 (1H, d, J=4.0 Hz), 8.29 (1H, s). [M+H] Calc'd for C₂₂H₁₉ClN₂O₃, 395; Found, 395.

Preparation 41a: methyl 3-({[(4S)-7-(3-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate, and Preparation 42a: methyl 3-({[(4R)-7-(3-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 14c (400 mg, 1.06 mmol) in dioxane (10 mL) was added 3-fluoro-2-methylphenylboronic acid (245 mg, 1.59 mmol), Pd(PPh₃)₄ (123 mg, 1.06 mmol) and Na₂CO₃ (338 mg, 3.18 mmol). The mixture was stirred at 110° C. overnight under nitrogen. The mixture was diluted with EtOAc, filtered, and concentrated. Purification by silica gel chromatography (PE:EtOAc=1:1) gave 170 mg (39%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₄H₂₃FN₂O₃, 407; Found, 407.

Separation by chiral HPLC (Column: Chiralcel IC, 250*4.6 mm 5 um; Mobile phase: Hex:EtOH=70:30; F: 1.0 mL/min; W: 230 nm; T=30° C.) gave 68 mg (32%) of Preparation 41a (6.921 min) and 68 mg (32%) of Preparation 42a (7.486 min), each as a yellow oil.

Example 41: 3-({[(4S)-7-(3-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 81% yield from Preparation 41a according to the general procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.91-2.05 (2H, m), 2.13 (3H, s), 3.18-3.22 (1H, m), 3.55-3.60 (1H, m), 3.74-3.79 (1H, m), 4.19-4.26 (2H, m), 6.74 (1H, s), 6.82-6.84 (1H, m), 7.04 (1H, d, J=8.0 Hz), 7.15 (1H, t, J=8.8 Hz), 7.24-7.30 (1H, m), 7.39 (1H, d, J=8.0 Hz), 7.60 (1H, d, J=5.2 Hz), 7.87 (1H, d, J=5.2 Hz), 8.46 (1H, s). [M+H] Calc'd for C₂₃H₂₁FN₂O₃, 393; Found, 393.

Example 42: 3-({[(4R)-7-(3-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 85% yield from Preparation 42a according to the general procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.94-2.13 (2H, m), 2.13 (3H, s), 3.18-3.21 (1H, m), 3.54-3.60 (1H, m), 3.74-3.79 (1H, m), 4.21-4.26 (2H, m), 6.74 (1H, s), 6.82-6.84 (1H, m), 7.04 (1H, d, J=7.6 Hz), 7.15 (1H, t, J=8.8 Hz), 7.24-7.30 (1H, m), 7.39 (1H, d, J=8.0 Hz), 7.59 (1H, d, J=4.8 Hz), 7.86 (1H, d, J=5.2 Hz), 8.46 (1H, s). [M+H] Calc'd for C₂₃H₂₁FN₂O₃, 393; Found, 393.

Preparation 43a: tert-butyl N-{[(4R)-7-(5-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

To a suspension of Preparation 18d (200 mg, 0.58 mmol), 5-fluoro-2-methylphenylboronic acid (135 mg, 0.88 mmol) and Na₂CO₃ (184 mg, 1.74 mmol) in dioxane (10 mL) and H₂O (0.5 mL) was added Pd(PPh₃)₄ (67 mg, 0.06 mmol) at rt under N₂. The reaction was stirred at 100° C. overnight. The reaction was filtered and purified by silica gel chromatography (PE:EtOAc=10:1) to give 150 mg (70%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₂H₂₆FNO₃, 372; Found, 372.

Preparation 43b: [(4R)-7-(5-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

To a solution of Preparation 43a (150 mg, 0.40 mmol) in EtOAc (5 mL) was added HCl/EtOAc (8 mL, 1.0 M) at rt, and the reaction was stirred for 2 h. The solution was concentrated, re-dissolved in EtOAc, and washed with sat. Na₂CO₃. The organic layer was dried (Na₂SO₄) and concentrated to give the title compound as a yellow oil. [M+H] Calc'd for C₁₇H₁₈FNO, 272; Found, 272.

Preparation 43c: methyl 3-({[(4R)-7-(5-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 49% yield from Preparation 43b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₃FN₂O₃, 407; Found, 407.

Example 43: 3-({[(4R)-7-(5-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 89% yield from Preparation 43c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.90-1.94 (1H, m), 2.01-2.05 (1H, m), 2.20 (3H, s), 3.17-3.21 (1H, m), 3.53-3.59 (1H, m), 3.74-3.79 (1H, m), 4.18-4.26 (2H, m), 6.75 (1H, d, J=1.6 Hz), 6.85 (1H, dd, J=1.6, 8.0 Hz), 6.98 (1H, dd, J=2.8, 9.6 Hz), 7.09 (1H, td, J=3.2, 8.8 Hz), 7.30 (1H, dd, J=5.6, 8.4 Hz), 7.39 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=4.8 Hz), 7.86 (1H, d, J=3.2 Hz), 8.44 (1H, s). [M+H] Calc'd for C₂₃H₂₁FN₂O₃, 393; Found, 393.

Preparation 44a: [(4R)-7-(2-chloro-3-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 78% yield from 2-chloro-3-fluorophenylboronic acid and Preparation 18d according to the procedures for Preparation 43a and 43b. [M+H] Calc'd for C₁₆H₁₅ClFNO, 292; Found, 292.

Preparation 44b: methyl 3-({[(4R)-7-(2-chloro-3-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 44a according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₃H₂₀ClFN₂O₃, 427; Found, 427.

Example 44: 3-({[(4R)-7-(2-chloro-3-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 48% yield from Preparation 44b according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.90-1.96 (m, 1H), 2.00-2.07 (m, 1H), 3.19-3.23 (m, 1H), 3.53-3.59 (m, 1H), 3.73-3.78 (m, 1H), 4.20-4.29 (m, 2H), 6.96 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.28-7.32 (m, 1H), 7.43-7.49 (m, 2H), 7.56-7.60 (m, 2H), 7.86 (d, J=5.2 Hz, 1H), 8.46 (s, 1H). [M+H] Calc'd for C₂₂H₁₈ClFN₂O₃, 413; Found, 413.

Preparation 45a: [(4R)-7-(2-chloro-5-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 77% yield from 2-chloro-5-fluorophenylboronic acid and Preparation 18d according to the procedures for Preparation 43a and 43b. [M+H] Calc'd for C₁₆H₁₅ClFNO, 292; Found, 292.

Preparation 45b: methyl 3-({[(4R)-7-(2-chloro-5-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 46% yield from Preparation 45a according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₃H₂₀ClFN₂O₃, 427; Found, 427.

Example 45: 3-({[(4R)-7-(2-chloro-5-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 52% yield from Preparation 45b according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.89-1.94 (m, 1H), 1.99-2.07 (m, 1H), 3.18-3.22 (m, 1H), 3.52-3.60 (m, 1H), 3.74-3.79 (m, 1H), 4.18-4.28 (m, 2H), 6.85 (d, J=1.2 Hz, 1H), 6.94 (dd, J=7.6 Hz, 1.2 Hz, 1H), 7.24-7.29 (m, 2H), 7.43 (d, J=7.6 Hz, 1H), 7.58-7.61 (m, 2H), 7.86 (d, J=4.8 Hz, 1H), 8.46 (s, 1H). [M+H] Calc'd for C₂₂H₁₈ClFN₂O₃, 413; Found, 413.

Preparation 46a: [(4R)-7-[2-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 59% yield from 2-(trifluoromethyl)phenylboronic acid and Preparation 18d according to the procedures for Preparation 43a and 43b. [M+H] Calc'd for C₁₇H₁₆F₃NO, 308; Found, 292.

Preparation 46b: methyl 3-({[(4R)-7-[2-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxyl

The title compound was prepared in 62% yield from Preparation 45a according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₁F₃N₂O₃, 443; Found, 443.

Example 46: 3-({[(4R)-7-[2-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 66% yield from Preparation 46b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.90-1.95 (1H, m), 2.01-2.05 (1H, m), 3.17-3.24 (1H, m), 3.52-3.60 (1H, m), 3.74-3.80 (1H, m), 4.20-4.26 (2H, m), 6.72 (1H, s), 6.81 (1H, d, J=7.5 Hz), 7.37-7.41 (2H, m), 7.58-7.62 (2H, m), 7.70 (1H, t, J=7.5 Hz), 7.80-7.87 (2H, m), 8.46 (1H, s). [M+H] Calc'd for C₂₃H₁₉F₃N₂O₃, 429; Found, 429.

Preparation 47a: 3-(3-phenoxyphenoxy)propanenitrile

To a solution of 3-phenoxyphenol (3.0 g, 16.1 mmol) in acetonitrile (10.6 mL, 161 mmol) was added tert-BuOH (120 mg, 1.6 mmol) and K₂CO₃ (225 mg, 1.6 mmol). The mixture was refluxed for 2 days. The reaction was filtered and concentrated, and the residue was purified by HPLC to get give 2.78 g (72%) of the title compound as a colorless gum. ¹H NMR (400 MHz, CDCl₃): δ 2.80 (2H, t, J=6.0 Hz), 4.15 (2H, t, J=6.0 Hz), 6.55 (1H, s), 6.64 (2H, d, J=8.0 Hz), 7.02 (2H, d, J=7.6 Hz), 7.12 (1H, t, J=7.2 Hz), 7.23 (1H, t, J=8.0 Hz) 7.35 (2H, t, J=8.0 Hz).

Preparation 47b: 7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-one

To a solution of Preparation 47a (2.78 g, 11.6 mmol) in TFA (4.5 mL) was slowly added TfOH (1.54 mL) under nitrogen at 0-5° C. The mixture was stirred at 0-5° C. for 3 h, and then at rt for 16 h. The reaction was cooled to 0° C. and quenched with water, stirring at rt for 3 h. The reaction was extracted with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated. The residue was purified by HPLC to give 2.5 g (89%) as a yellow gum. ¹H NMR (300 MHz, DMSO-d₆): δ 2.73 (2H, t, J=6.3 Hz), 4.50 (2H, t, J=6.6 Hz), 6.42 (1H, s), 6.62 (1H, d, J=8.7 Hz), 7.13 (2H, d, J=7.8 Hz), 7.26 (1H, t, J=7.2 Hz), 7.46 (2H, t, J=8.1 Hz) 7.75 (1H, d, J=8.7 Hz). [M+H] Calc'd for C₁₅H₁₂O₃, 241; Found, 241.

Preparation 47c: (7-phenoxy-2H-chromen-4-yl)methanamine

The title compound was prepared in 65% yield from Preparation 47b according to the general procedure for Preparation 16a. ¹H NMR (400 MHz, MeOD-d₄): δ 3.89 (2H, s), 4.72 (2H, d, J=4.0 Hz), 5.86 (1H, t, J=3.6 Hz), 6.35 (1H, s), 6.49 (1H, d, J=6.0 Hz), 6.94 (2H, d, J=3.6 Hz), 7.08 (1H, d, J=7.6 Hz), 7.15 (1H, d, J=8.8 Hz), 7.30 (2H, t, J=8.0 Hz). [M+H] Calc'd for C₁₆H₁₅NO₂, 254; Found, 254.

Preparation 47d: (7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl)methanamine

To a solution of Preparation 47c (1.5 g, 6.0 mmol) in MeOH (150 mL) and one drop of conc. HCl under N₂ was added 10% Pd/C (250 mg) at rt. The suspension was stirred for 16 h at rt under H₂. The reaction mixture was filtered through Celite, and the pH was adjusted to 8˜9 with sat. Na₂CO₃. The solution was dried (Na₂SO₄) and concentrated to give 1.0 g (67%) of the title compound as a yellow gum. [M+H] Calc'd for C₁₆H₁₇NO₂, 256; Found, 256.

Preparation 47e: methyl 3-{[(7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 15% yield from Preparation 47d according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₃H₂₂N₂O₄, 390; Found, 390.

Preparation 47f: methyl 3-({[(4S)-7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 48f: methyl 3-({[(4R)-7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

Preparation 47e (120 mg) was purified by chiral HPLC (Column: Chiralcel IA, 250 mm*4.6 mm 5 um; Mobile phase: Hex:EtOH=60:40; F: 1.0 mL/min; W: 230 nm; T=30° C.) to give 43 mg (36%) of Preparation 48f (7.36 min) and 45 mg (38%) of Preparation 47f (10.26 min), each as a pale-yellow oil.

Example 47: 3-({[(4S)-7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 74% yield from Preparation 47f according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.84-1.88 (1H, m), 1.95-2.03 (1H, m), 3.13-3.17 (1H, m), 3.53-3.59 (1H, m), 3.72-3.77 (1H, m), 4.14-4.25 (2H, m), 6.37 (1H, s), 6.50 (1H, d, J=8.4 Hz), 6.99 (2H, d, J=8.0 Hz), 7.12-7.16 (1H, m), 7.32-7.41 (3H, m), 7.94 (2H, s), 8.55 (1H, s). [M+H] Calc'd for C₂₂H₂₀N₂O₄, 377; Found, 377.

Example 48: 3-({[(4R)-7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 77% yield from Preparation 48f according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.86-1.89 (1H, m), 1.97-2.01 (1H, m), 3.14-3.16 (1H, m), 3.52-3.57 (1H, m), 3.73-3.77 (1H, m), 4.13-4.25 (2H, m), 6.37 (1H, s), 6.50 (1H, d, J=8.0 Hz), 6.99 (2H, d, J=8.0 Hz), 7.12-7.15 (1H, m), 7.32-7.41 (3H, m), 7.95 (2H, s), 8.56 (1H, s). [M+H] Calc'd for C₂₂H₂₀N₂O₄, 377; Found, 377.

Preparation 49a: 7-(thiophen-2-ylsulfanyl)-3,4-dihydro-2H-1-benzopyran-4-one

7-Bromochroman-4-one (1.5 g, 6.6 mmol), thiophene-2-thiol (0.68 mL, 7.3 mmol), and potassium carbonate (1.37 g, 9.9 mmol) were combined in ACN (50 mL) in a sealed vessel, and the reaction was heated at 78° C. overnight. The reaction was cooled, filtered, and concentrated. Purification by silica gel chromatography (10-60% EtOAc/hexanes) gave 1.6 g (93%) of the title compound as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆): δ 2.75 (2H, t, J=6.4 Hz), 4.48 (2H, t, J=6.4 Hz), 6.59 (1H, d, J=1.8 Hz), 6.75 (1H, dd, J=8.4, 1.8 Hz), 7.13-7.17 (1H, m), 7.34 (1H, dd, J=3.6, 1.2 Hz), 8.58 (1H, dd, J=5.4, 1.2 Hz), 7.75 (1H, d, J=8.4 Hz). [M+H] calc'd for C₁₃H₁₀O₂S₂, 263; found 263.

Preparation 49b: [7-(thiophen-2-ylsulfanyl)-2H-chromen-4-yl]methanamine, Hydrochloride

The title compound was prepared in 25% yield from Preparation 49a according to the general procedure for Preparation 3a. [M+H] calc'd for C₁₄H₁₃NOS₂, 276; found 276.

Preparation 49c: [7-(thiophen-2-ylsulfanyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in quantitative yield from Preparation 49b according to the general procedure for Preparation 3e. [M+H] calc'd for C₁₄H₁₅NOS₂, 278; found 278.

Example 49: 3-({[7-(thiophen-2-ylsulfanyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 5% yield from Preparation 49c according to the general procedure for Example 13. ¹H NMR (400 MHz, DMSO-d₆): δ 1.86-1.98 (2H, m), 3.06-3.10 (1H, m), 3.43-3.49 (1H, m), 3.61-3.67 (1H, m), 4.10-4.20 (2H, m), 6.50 (1H, d, J=1.8 Hz), 6.69 (1H, dd, J=8.0, 1.8 Hz), 7.17 (1H, dd, J=5.3, 3.6 Hz), 7.26 (1H, d, J=8.1 Hz), 7.39-7.42 (1H, m), 7.57 (1H, d, J=4.4 Hz), 7.81 (1H, d, J=4.4 Hz), 7.82 (1H, d, J=0.9 Hz), 8.37 (1H, s). [M+H] calc'd for C₂₀H₁₈N₂O₃S, 399; found 399.

Preparation 50a: tert-butyl N-({7-[(2-methylphenyl)sulfanyl]-2H-chromen-4-yl}methyl)carbamate

To a suspension of Preparation 16a (1.2 g, 3.5 mmol), 2-methylthiophenol (438 mg, 3.53 mmol) and Xantphos (102 mg, 0.176 mmol) in dioxane (25 mL) and DIEA (1.2 mL, 7.0 mmol) was added Pd₂dba₃ (82 mg, 0.088 mmol) at rt under N₂. The reaction was stirred at reflux overnight. The reaction was filtered and concentrated. Purification by silica gel chromatography (PE:EtOAc=5:1) gave 483 mg (36%) as an orange oil. [M+H] Calc'd for C₂₂H₂₅NO₃S, 384; Found, 384.

Preparation 50b: tert-butyl N-({7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)carbamate

To a solution of Preparation 50a (483 mg, 1.26 mmol) in MeOH (10 mL) and AcOH (2 mL) was added 10% Pd/C (150 mg) at rt. The mixture was stirred overnight with 50 psi H₂. The reaction was filtered and concentrated. The residue was dissolved in EtOAc, washed with sat. Na₂CO₃, dried (Na₂SO₄), and concentrated to give 450 mg (93%) of the title compound as a pale brown oil. [M+H] Calc'd for C₂₂H₂₇NO₃S, 386; Found, 386.

Preparation 50c: {7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methanamine

To a solution of Preparation 50b (450 mg, 1.17 mmol) in EtOAc (10 mL) was added HCl/EtOAc (10 mL, 1.0 M), and the reaction stirred at rt overnight. The solution was concentrated, and the residue was dissolved in EtOAc, washed with sat. Na₂CO₃, dried (Na₂SO₄), and concentrated to give 320 mg (96%) of the title compound as an orange oil. [M+H] Calc'd for C₁₇H₁₉NOS, 286; Found, 286.

Preparation 50d: methyl 3-({[(4S)-7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 51d: methyl 3-({[(4R)-7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The racemate (150 mg) of the title compounds was prepared in 32% yield from Preparation 50c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₄H₂₄N₂O₃S, 421; Found, 421.

Separation by chiral HPLC (Column: Chiralcel: IA Sum 4.6*250 mm, Mobile phase: Hex:EtOH=50:50, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 60 mg (40%) of Preparation 51d (7.746 min) and 62 mg (41%) of Preparation 50d (10.602 min), each as a yellow oil.

Example 50: 3-({[(4S)-7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 76% yield from Preparation 56d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.84-1.88 (1H, m), 1.94-1.99 (1H, m), 2.31 (3H, s), 3.10-3.13 (1H, m), 3.48-3.54 (1H, m), 3.66-3.70 (1H, m), 4.12-4.22 (2H, m), 6.50 (1H, s), 6.67-6.70 (1H, m), 7.20-7.35 (5H, m), 7.57 (1H, d, J=5.2 Hz), 7.85 (1H, d, J=4.8 Hz), 8.41 (1H, s). [M+H] Calc'd for C₂₃H₂₂N₂O₃S, 407; Found, 407.

Example 51: 3-({[(4R)-7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 90% yield from Preparation 51d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.86-1.88 (1H, m), 1.96-1.98 (1H, m), 2.31 (3H, s), 3.10-3.13 (1H, m), 3.48-3.54 (1H, m), 3.66-3.71 (1H, m), 4.14-4.19 (2H, m), 6.50 (1H, s), 6.68-6.70 (1H, m), 7.22-7.35 (5H, m), 7.58 (1H, d, J=5.2 Hz), 7.85 (1H, d, J=5.2 Hz), 8.41 (1H, s). [M+H] Calc'd for C₂₃H₂₂N₂O₃S, 407; Found, 407.

Preparation 52a: methyl 3-[({7-[(3-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)amino]pyridine-4-carboxylate

To a solution of Preparation 14c (310 mg, 0.82 mmol) in THF (5 mL) was added 3,3′-difluorodiphenyldisulfide (105 mg, 0.41 mmol), Pd(dppf)Cl₂ (34 mg, 0.041 mmol) and Zn (65 mg, 0.99 mmol). The mixture was stirred at reflux for overnight under nitrogen. The mixture was diluted with EtOAc, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=1:1) to give 112 mg (32%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₃H₂₁F₂O₃S, 425; Found, 425.

Preparation 52b: methyl 3-({[(4S)-7-[(3-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 53b: methyl 3-({[(4R)-7-[(3-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

Preparation 52a (112 mg) was separated by chiral HPLC (Column: Chiralcel IA, 250 mm*4.6 mm 5 um; Mobile phase: Hex:EtOH=50:50; F: 1.0 mL/min; W: 230 nm; T=30° C.) to give 44 mg (29%) of Preparation 53b (7.697 min) and 43 mg (29%) of Preparation 52b (10.724 min), each as a yellow oil.

Example 52: 3-({[(4S)-7-[(3-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 78% yield from Preparation 52b according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.90-2.01 (2H, m), 3.15-3.18 (1H, m), 3.51-3.57 (1H, m), 3.69-3.74 (1H, m), 4.18-4.24 (2H, m), 6.81 (1H, s), 6.89-6.92 (1H, m), 7.07-7.14 (3H, m), 7.37-7.42 (2H, m), 7.58 (1H, d, J=4.8 Hz), 7.86 (1H, d, J=4.8 Hz), 8.43 (1H, s). [M+H] Calc'd for C₂₂H₁₉FN₂O₃S, 411; Found, 411.

Example 53: 3-({[(4R)-7-[(3-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 68% yield from Preparation 53b according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.90-2.01 (2H, m), 3.15-3.18 (1H, m), 3.51-3.57 (1H, m), 3.69-3.74 (1H, m), 4.18-4.24 (2H, m), 6.81 (1H, s), 6.89-6.91 (1H, m), 7.07-7.14 (3H, m), 7.37-7.43 (2H, m), 7.57 (1H, d, J=4.8 Hz), 7.85 (1H, d, J=5.2 Hz), 8.42 (1H, s). [M+H] Calc'd for C₂₂H₁₉FN₂O₃S, 411; Found, 411.

Preparation 54a: methyl 3-[({7-[(4-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)amino]pyridine-4-carboxylate

The title compound was prepared in 53% yield from 3,3′-difluorodiphenyldisulfide according to the general procedure for Preparation 52a. [M+H] Calc'd for C₂₃H₂₁F₂O₃S, 425; Found, 425.

Preparation 54b: methyl 3-({[(4S)-7-[(4-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 55b: methyl 3-({[(4R)-7-[(4-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

Preparation 54a (179 mg) was separated by chiral HPLC (Column: Chiralcel IA, 250 mm*4.6 mm 5 um; Mobile phase: Hex:EtOH=50:50; F: 1.0 mL/min; W: 230 nm; T=30° C.) to give 70 mg (41%) of Preparation 55b (9.350 min) and 70 mg (41%) of Preparation 54b (16.515 min), each as a yellow oil.

Example 54: 3-({[(4S)-7-[(4-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 86% yield from Preparation 54b according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.84-1.98 (2H, m), 3.11-3.14 (1H, m), 3.48-3.54 (1H, m), 3.66-3.70 (1H, m), 4.13-4.20 (2H, m), 6.62 (1H, s), 6.75-6.78 (1H, m), 7.24-7.32 (3H, m), 7.41-7.45 (2H, m), 7.59 (1H, d, J=5.2 Hz), 7.86 (1H, d, J=4.8 Hz), 8.42 (1H, s). [M+H] Calc'd for C₂₂H₁₉FN₂O₃S, 411; Found, 411.

Example 55: 3-({[(4R)-7-[(4-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 85% yield from Preparation 55b according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.84-2.00 (2H, m), 3.15-3.18 (1H, m), 3.48-3.54 (1H, m), 3.66-3.70 (1H, m), 4.13-4.22 (2H, m), 6.62 (1H, s), 6.76-6.78 (1H, m), 7.24-7.32 (3H, m), 7.41-7.45 (2H, m), 7.58 (1H, d, J=5.2 Hz), 7.85 (1H, d, J=5.2 Hz), 8.41 (1H, s). [M+H] Calc'd for C₂₂H₁₉FN₂O₃S, 411; Found, 411

Preparation 56a: 6-[(6-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydronaphthalen-1-one

A suspension of 6-hydroxy-1-tetralone (3.0 g, 18 mmol), 2-fluoro-6-methylpyridine (2.06 g, 18.5 mmol) and Cs₂CO₃ (12.1 g, 37.0 mmol) in DMF (150 mL) was stirred at 150° C. in a sealed vessel overnight under N₂. The reaction was poured into water (300 mL) and extracted with EtOAc (3×50 mL). Organics were dried (Na₂SO₄) and concentrated. Purification by silica gel chromatography (PE:EA=5:1) gave 1.2 g (26%) of the title compound as a red oil. [M+H] calc'd for C₁₆H₁₅NO₂, 254; found 254.

Preparation 56b: {6-[(6-methylpyridin-2-yl)oxy]-3,4-dihydronaphthalen-1-yl}methanamine, Hydrochloride

The title compound was prepared in 71% yield from Preparation 56a according to the general procedure for Preparation 3a. [M+H] calc'd for C₁₇H₁₈N₂O, 267; found 267.

Preparation 56c: {6-[(6-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in quantitative yield from Preparation 56b according to the general procedure for Preparation 3e. [M+H] calc'd for C₁₇H₂₀N₂O, 269; found 269.

Preparation 56d: methyl 3-[({6-[(6-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)amino]pyridine-4-carboxylic Acid

The title compound was prepared in 66% yield from Preparation 56c according to the procedure for Preparation 1e. [M+H] Calc'd for C₂₄H₂₅N₃O₃, 404; Found, 404.

Example 56: 3-[({6-[(6-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)amino]pyridine-4-carboxylic Acid

The title compound was prepared in 42% yield from Preparation 56d according to the general procedure for Example 1. ¹H NMR (400 MHz, MeOD-d₄): δ 1.80-1.82 (1H, m), 1.97-2.01 (3H, m), 2.45 (3H, s), 2.81-2.85 (2H, m), 3.21-3.24 (1H, m), 3.51-3.66 (2H, m), 6.57 (1H, d, J=8.0 Hz), 6.86-6.88 (2H, m), 7.00 (1H, d, J=7.2 Hz), 7.34 (1H, d, J=9.2 Hz), 7.68 (1H, t, J=8.0 Hz), 7.83-7.89 (2H, m), 8.21 (1H, s). [M+H] Calc'd for C₂₃H₂₃N₃O₃, 390; Found, 390.

Preparation 57a: 6-amino-1,2,3,4-tetrahydronaphthalen-1-one

The suspension of 6-amino-1,2,3,4-tetrahydronaphthalen-1-one (1.0 g, 4.4 mmol), o-cresol (0.72 g, 6.7 mmol), 1-pyridin-2-ylacetone (0.12 g, 0.89 mmol), Cs₂CO₃ (2.9 g, 8.9 mmol) and CuBr (70 mg, 0.44 mmol) in DMSO (10 mL) was stirred at 110° C. overnight under N₂. The reaction was poured into water and extracted with EtOAc. Organics were dried (Na₂SO₄) and concentrated. Purification by silica gel chromatography (PE:EtOAc=30:1 to 10:1) gave 0.77 g (69%) of the title compound as a colorless oil. ¹H NMR (300 MHz, CDCl₃): δ 2.07-2.15 (m, 2H), 2.19 (s, 3H), 2.62 (t, J=6.3 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 6.66 (s, 1H), 6.77 (dd, J=8.7 Hz, 2.7 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 7.11-7.30 (m, 3H), 8.01 (d, J=8.7 Hz, 1H). [M+H] Calc'd for C₁₇H₁₆O₂, 253; Found, 253.

Preparation 57b: [6-(2-methylphenoxy)-3,4-dihydronaphthalen-1-yl]methanamine, Hydrochloride

The title compound was prepared in 73% yield from Preparation 57a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₈H₁₉NO, 266; Found, 266.

Preparation 57c: [6-(2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 93% yield from Preparation 57b according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₈H₂₁NO, 268; Found, 268.

Preparation 57d: methyl 3-({[(1S)-6-(2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 58d: methyl 3-({[(1R)-6-(2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (300 mg) of the title compounds was prepared in 26% yield from Preparation 72c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₅H₂₆N₂O₃, 403; Found, 403.

Separation by chiral HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 108 mg (36%) of Preparation 57a (6.053 min) and 108 mg (36%) of Preparation 58a (6.873 min) as a colorless oil.

Example 57: 3-({[(1S)-6-(2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 67% yield from Preparation 57d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.63-1.67 (m, 1H), 1.78-1.84 (m, 3H), 2.17 (s, 3H), 2.63-2.73 (m, 2H), 3.06-3.09 (m, 1H), 3.42-3.47 (m, 1H), 3.55-3.59 (m, 1H), 6.61 (d, J=2.0 Hz, 1H), 6.65 (dd, J=6.4 Hz, 2.4 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 7.07-7.10 (m, 1H), 7.18-7.22 (m, 1H), 7.28-7.31 (m, 2H), 7.56 (d, J=5.2 Hz, 1H), 7.83 (d, J=5.2 Hz, 1H), 8.35 (s, 1H). [M+H] Calc'd for C₂₄H₂₄N₂O₃, 389; Found, 389.

Example 58: 3-({[(1R)-6-(2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 81% yield from Preparation 58d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.63-1.67 (m, 1H), 1.78-1.84 (m, 3H), 2.17 (s, 3H), 2.63-2.73 (m, 2H), 3.06-3.09 (m, 1H), 3.42-3.47 (m, 1H), 3.55-3.59 (m, 1H), 6.61 (d, J=2.0 Hz, 1H), 6.65 (dd, J=6.4 Hz, 2.4 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 7.06-7.10 (m, 1H), 7.18-7.22 (m, 1H), 7.28-7.31 (m, 2H), 7.56 (d, J=5.2 Hz, 1H), 7.83 (d, J=5.2 Hz, 1H), 8.35 (s, 1H). [M+H] Calc'd for C₂₄H₂₄N₂O₃, 389; Found, 389.

Preparation 59a: 6-propoxy-1,2,3,4-tetrahydronaphthalen-1-one

6-Hydroxy-1-tetralone (2.0 g, 12.3 mmol), bromo-propane (2.24 mL, 24.7 mmol), potassium iodide (2.05 g, 12.3 mmol) and potassium carbonate (3.41 g, 24.7 mmol) were combined in ACN (50 mL) in a sealed vessel, and the reaction was stirred at 122° C. overnight. The reaction was cooled, filtered, and concentrated. Purification by silica gel chromatography (10-50% EtOAc/hexanes) gave 2.36 g (94%) of the title compound as a clear oil. ¹H NMR (400 MHz, DMSO-d₆): δ 1.04 (3H, t, J=7.4 Hz), 1.79-1.85 (2H, m), 2.09-2.14 (2H, m), 2.60 (2H, t, J=6.3 Hz), 2.88-2.93 (2H, t, J=6.5 Hz), 3.97 (2H, t, J=6.5 Hz), 6.69 (1H, d, J=2.3 Hz), 6.81 (1H, dd, J=8.8, 4.1 Hz), 7.99 (1H, d, J=8.7 Hz). [M+H] calc'd for C₁₃H₁₆O₂, 205; found 205.

Preparation 59b: (6-propoxy-3,4-dihydronaphthalen-1-yl)methanamine, Hydrochloride

The title compound was prepared in 54% yield from Preparation 59a according to the general procedure for Preparation 3a. [M+H] calc'd for C₁₄H₁₈NO, 218; found 218.

Preparation 59c: (6-propoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in quantitative yield from Preparation 59b according to the general procedure for Preparation 3e. [M+H] calc'd for C₁₄H₂₀NO, 220; found 220.

Example 59: 3-{[(6-propoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic Acid

The title compound was prepared in 26% yield from Preparation 59c according to the general procedure for Example 13. ¹H NMR (400 MHz, DMSO-d₆): δ 0.96 (3H, t, J=7.4 Hz), 1.65-1.82 (6H, m), 2.66-2.71 (2H, m), 3.02-3.05 (1H, m), 3.38-3.55 (2H, m), 3.87 (2H, t, J=6.5 Hz), 6.64-6.71 (2H, m), 7.20 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=5.0 Hz), 7.70 (1H, br s), 7.83 (1H, d, J=5.0 Hz), 8.35 (1H, s), 13.40 (1H, br s). [M+H] calc'd for C₂₀H₂₄N₂O₃, 341; found 341.

Preparation 60a: 6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-one

A solution of 6-hydroxy-1-tetralone (5.0 g, 30.8 mmol) in DMA (75 mL) was cooled to 0° C. Freon was bubbled into the mixture for 10 min. Cs₂CO₃ (30.1 g, 92.5 mmol) was added, and the reaction was heated at 50° C. in a sealed vessel for 2 h. The mixture poured into ice-water and extracted with EtOAc. Organics were dried and concentrated. Purification by silica gel chromatography (PE:EtOAc=10:1 to 5:1) gave 5.1 g (78%) of the title compound as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 2.11-2.17 (m, 2H), 2.65 (t, J=6.4 Hz, 2H), 2.96 (t, J=6.0 Hz, 2H), 6.59 (t, J=73.2 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 7.01 (dd, J=8.4 Hz, 2.0 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H).

Preparation 60b: [6-(difluoromethoxy)-3,4-dihydronaphthalen-1-yl]methanamine, Hydrochloride

The title compound was prepared in 53% yield from Preparation 60a according to the general procedure for Preparation 3a. [M+H] calc'd for C₁₂H₁₃F₂NO, 226; found 226.

Preparation 60c: [6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 85% yield from Preparation 60b according to the general procedure for Preparation 3e. [M+H] calc'd for C₁₂H₁₅F₂NO, 228; found 228.

Preparation 60d: methyl 3-({[(1S)-6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 61d: methyl 3-({[(1R)-6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 25% yield from Preparation 60c according to the general procedure for Preparation 1e.

Separation by chiral HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 20% yield of Preparation 60d (6.240 min) and 16% yield of Preparation 61d (6.718 min), each as a colorless oil.

Example 60: 3-({[(1S)-6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 71% yield from Preparation 60d according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.65-1.70 (m, 1H), 1.76-1.87 (m, 3H), 2.67-2.80 (m, 2H), 3.08-3.14 (m, 1H), 3.43-3.48 (m, 1H), 3.55-3.60 (m, 1H), 6.92-6.95 (m, 2H), 7.18 (t, J=74.8 Hz, 1H), 7.36 (s, 1H), 7.56 (d, J=4.8 Hz, 1H), 7.84 (d, J=4.8 Hz, 1H), 8.38 (s, 1H).

[M+H] Calc'd for C₁₈H₁₈F₂N₂O₃, 349; Found, 349.

Example 61: 3-({[(1R)-6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 78% yield from Preparation 61d according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.64-1.71 (m, 1H), 1.74-1.88 (m, 3H), 2.67-2.80 (m, 2H), 3.09-3.12 (m, 1H), 3.42-3.48 (m, 1H), 3.55-3.60 (m, 1H), 6.92-6.95 (m, 2H), 7.18 (t, J=74.4 Hz, 1H), 7.36 (s, 1H), 7.56 (d, J=4.8 Hz, 1H), 7.84 (d, J=4.8 Hz, 1H), 8.38 (s, 1H).

[M+H] Calc'd for C₁₈H₁₈F₂N₂O₃, 349; Found, 349.

Preparation 62a: 6-[2-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 6-hydroxy-1-tetralone (2.5 g, 15.4 mmol) and 2-iodobenzotrifluoride (25 g, 92 mmol) in DMF (50 mL) was added NaH (0.74 g, 60%, 18.5 mmol) at rt. The mixture was heated to 50° C. until the solid was dissolved and then cooled. To the mixture was added CuCl (1.53 g, 15.4 mmol), followed by tris(dioxa 3,6-heptyl)amine (1.65 mL, 5.15 mmol). The mixture was heated at 145° C. overnight. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated. Purification by silica gel chromatography (0-20% EtOAc/hexanes) gave 850 mg (18%) of the title compound as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 2.09-2.16 (2H, m), 2.63 (2H, t, J=6.2 Hz), 2.91 (2H, t, J=6.1 Hz), 6.82 (1H, d, J=2.4 Hz), 6.86 (dd, 1H, J=8.6, 2.4 Hz), 7.05 (1H, d, J=8.2 Hz), 7.27 (1H, td, J=8.2, 0.6 Hz), 7.51-7.56 (1H, m), 7.71 (1H, dd, J=7.8, 1.2 Hz), 8.07 (1H, d, J=8.2 Hz). [M+H] calc'd for C₁₇H₁₃F₃O₂, 307; found 307.

Preparation 62b: {6-[2-(trifluoromethyl)phenoxy]-3,4-dihydronaphthalen-1-yl}methanamine, Hydrochloride

The title compound was prepared in 58% yield from Preparation 62a according to the general procedure for Preparation 3a. [M+H] calc'd for C₁₈H₁₆F₃NO, 320; found 320.

Preparation 62c: {6-[2-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in quantitative yield from Preparation 62b according to the general procedure for Preparation 3e. ¹H NMR (400 MHz, CD₃OD): δ 1.68-1.92 (4H, m), 2.68-2.72 (2H, m), 2.82-2.96 (3H, m), 6.72 (1H, d, J=2.2 Hz), 6.78 (1H, dd, J=8.3, 2.4 Hz), 6.90 (1H, d, J=8.2 Hz), 7.15-7.23 (2H, m), 7.47 (1H, t, J=7.2 Hz), 7.66 (1H, d, J=7.6 Hz). [M+H] calc'd for C₁₈H₁₈F₃NO, 322; found 322.

Example 62: 3-[({6-[2-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)amino]pyridine-4-carboxylic Acid

The title compound was prepared in 15% yield from Preparation 62c according to the general procedure for Example 13. ¹H NMR (400 MHz, DMSO-d₆): δ 1.66-1.85 (4H, m), 2.67-2.79 (2H, m), 3.11-3.14 (1H, m), 3.44-3.63 (2H, m), 6.80-6.82 (2H, m), 6.98 (1H, d, J=8.4), 7.29 (1H, t, J=7.6 Hz), 6.37 (1H, d, J=9.2 Hz), 7.5 (1H, d, J=5.0 Hz), 7.63 (1H, t, J=7.4 Hz), 7.70 (1H, br s), 7.76 (1H, d, J=7.8 Hz), 7.83 (1H, d, J=5.0 Hz), 8.36 (1H, s), 13.34 (1H, br s). [M+H] calc'd for C₂₄H₂₁F₃N₂O₃, 443; found 443.

Preparation 63a: 6-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydronaphthalen-1-one

To a suspension of 6-hydroxy-1-tetralone (2.0 g, 12.4 mmol), tetrahydropyran-4-methanol (1.7 g, 14.8 mmol) and triphenylphosphine (6.5 g, 24.7 mmol) in THF (40 mL) was added DEAD (4.3 g, 24.7 mmol) at 0° C. The reaction was stirred at rt overnight. The solution was concentrated and purified by silica gel chromatography (PE:EtOAc=12:1) to give 3.2 g (100%) of the title compound as a yellow oil. [M+H] Calc'd for C₁₆H₂₀O₃, 261; Found, 261.

Preparation 63b: [6-(oxan-4-ylmethoxy)-3,4-dihydronaphthalen-1-yl]methanamine, Hydrochloride

The title compound was prepared in 71% yield from Preparation 63a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₇H₂₃NO₂, 274; Found, 274.

Preparation 63c: [6-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in quantitative yield from Preparation 63b according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₇H₂₅NO₂, 276; Found, 276.

Example 63: 3-({[6-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 5% yield from Preparation 63c according to the general procedure for Example 13. ¹H NMR (300 MHz, DMSO-d₆): δ 1.28-1.33 (2H, m), 1.64-1.77 (6H, m), 1.80-1.84 (1H, m), 2.67-2.70 (2H, m), 3.03-3.05 (1H, m), 3.28-3.45 (3H, m), 3.51-3.52 (1H, m), 3.77 (2H, d, J=6.3 Hz), 3.84-3.89 (2H, m), 6.65-6.71 (2H, m), 7.20 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=5.4 Hz), 7.82 (1H, d, J=5.4 Hz), 8.35 (1H, s). [M+H] Calc'd for C₂₃H₂₈N₂O₄, 397; Found, 397.

Preparation 64a: 6-(4-fluoro-2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-one

To a suspension of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (2.0 g, 8.9 mmol), 4-fluoro-2-methylphenol (1.7 g, 13.3 mmol), 1-pyridin-2-ylacetone (240 mg, 1.8 mmol) and Cs₂CO₃ (5.8 g, 17.8 mmol) in DMSO (40 mL) was added CuBr (127 mg, 0.9 mmol) at rt under N₂. The reaction was stirred at 100° C. overnight. The reaction was cooled, diluted with water (50 mL), and extracted with EtOAc (3×50 mL). Organics were washed with water (3×50 mL) and brine (50 mL), dried (Na₂SO₄), and concentrated. Purification by silica gel chromatography (PE:EtOAc=30:1) gave 2.3 g (95%) of the title compound as a colorless oil. [M+H] Calc'd for C₁₇H₁₅FO₂, 271; Found, 271.

Preparation 64b: 6-(4-fluoro-2-methylphenoxy)-3,4-dihydronaphthalene-1-carboxamide

To a solution of Preparation 64a (2.3 g, 8.4 mmol) in toluene (20 mL) was added ZnI₂ (20 mg) and TMSCN (2.2 mL, 16.8 mmol) at rt, and the solution was stirred at 60° C. overnight. The reaction was cooled to rt. H₂SO₄ (1.0 mL) was added, followed by AcOH (12 mL), H₂SO₄ (4.3 mL), and H₂O (1.3 mL). The reaction was heated to 130° C. for 6 h. The solution was cooled, diluted with H₂O (50 mL), and extracted with EtOAc (3×50 mL). Organics were washed with brine (50 mL), dried (Na₂SO₄), and concentrated. Purification by silica gel chromatography (PE:THF=1:1) gave 500 mg (20%) of the title compound as a white solid. [M+H] Calc'd for C₁₈H₁₆FNO₂, 298; Found, 298.

Preparation 64c: (1R)-6-(4-fluoro-2-methylphenoxy)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

To a solution of Preparation 64b (400 mg, 1.4 mmol) in MeOH (10 mL) and THF (10 mL) was added Ru(OAc)₂[s-binap] (5 mg) at rt. The mixture was heated at 50° C. for 2 days with 2.5 MPa H₂. The reaction was concentrated and the resulting solid was re-crystallized from EtOAc to give 120 mg (30%) of the title compound as a white solid. [M+H] Calc'd for C₁₈H₁₈FNO₂, 300; Found, 300. Column: Chiralcel AS-H, Mobile phase: 70:30 CO₂:MeOH (0.2DEA), ee=97%, 3.04 min.

Preparation 64d: [(1R)-6-(4-fluoro-2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

To a solution of Preparation 64c (150 mg, 0.50 mmol) in THF (10 mL) was added BH₃.THF (2.5 mL, 1.0 M, 2.5 mmol) at rt. The mixture was heated at 55° C. for 6 h. The reaction was cooled, diluted with water (10 mL), basified to pH 9 with sat. Na₂CO₃, and extracted with EtOAc (3×50 mL). Organics were washed with brine (50 mL), dried (Na₂SO₄), and concentrated to give 160 mg (quant.) of the crude title compound as a yellow oil. [M+H] Calc'd for C₁₈H₂₀FNO, 286; Found, 286.

Preparation 64e: methyl 3-({[(1R)-6-(4-fluoro-2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a suspension of Preparation 64d (0.50 mmol), methyl 3-bromoisonicotinate (119 mg, 0.55 mmol), Xantphos (43 mg, 0.08 mmol) and Cs₂CO₃ (228 mg, 0.70 mmol) in toluene (15 mL) was added Pd₂dba₃ (23 mg, 0.03 mmol) at rt under N₂. The reaction was stirred at 100° C. for 2 h. The reaction was filtered and concentrated. Purification by silica gel chromatography (PE:EtOAc=5:1) gave 88 mg (42%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₅H₂₅FN₂O₃, 421; Found, 421.

Example 64: 3-({[(1R)-6-(4-fluoro-2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 60% yield from Preparation 64e according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.64-1.67 (1H, m), 1.77-1.83 (3H, m), 2.16 (3H, s), 2.65-2.68 (2H, m), 3.05-3.09 (1H, m), 3.40-3.46 (1H, m), 3.54-3.59 (1H, m), 6.59 (1H, s), 6.63 (1H, dd, J=2.8, 8.4 Hz), 6.92 (1H, dd, J=5.2, 8.8 Hz), 7.04 (1H, td, J=2.8, 8.4 Hz), 7.19 (1H, dd, J=2.8, 8.2 Hz), 7.28 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=5.2 Hz), 7.82 (1H, d, J=4.8 Hz), 8.34 (1H, s). [M+H] Calc'd for C₂₄H₂₃FN₂O₃, 407; Found, 407.

Preparation 65a: 6-(2,4-difluorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 65% yield from 2,4-difluorophenol according to the procedure for Preparation 64a. [M+H] Calc'd for C₁₆H₁₂F₂O₂, 275; Found, 275.

Preparation 65b: 6-(2,4-difluorophenoxy)-3,4-dihydronaphthalene-1-carboxamide

The title compound was prepared in 44% yield from Preparation 65a according to the procedure for Preparation 64b. [M+H] Calc'd for C₁₇H₁₃F₂NO₂, 302; Found, 302.

Preparation 65c: (1R)-6-(2,4-difluorophenoxy)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

The title compound was prepared in 46% yield from Preparation 65b according to the procedure for Preparation 64c. [M+H] Calc'd for C₁₇H₁₅F₂NO₂, 304; Found, 304.

Preparation 65d: [(1R)-6-(2,4-difluorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 89% yield from Preparation 65c according to the procedure for Preparation 64d. [M+H] Calc'd for C₁₇H₁₇F₂NO, 290; Found, 290.

Preparation 65e: methyl 3-({[(1R)-6-(2,4-difluorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 52% yield from Preparation 65d according to the procedure for Preparation 64e. [M+H] Calc'd for C₂₄H₂₂F₂N₂O₃, 425; Found, 425.

Preparation 65: 3-({[(1R)-6-(2,4-difluorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 67% yield from Preparation 65e according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.64-1.67 (1H, m), 1.80-1.83 (3H, m), 2.66-2.69 (2H, m), 3.06-3.09 (1H, m), 3.40-3.45 (1H, m), 3.53-3.58 (1H, m), 6.67 (1H, d, J=2.4 Hz), 6.71-6.74 (1H, m), 7.11-7.13 (1H, m), 7.19-7.25 (1H, s), 7.30 (1H, d, J=8.4 Hz), 7.44-7.49 (1H, m), 7.55 (1H, d, J=5.2 Hz), 7.81 (1H, d, J=5.2 Hz), 8.33 (1H, s). [M+H] Calc'd for C₂₃H₂₀F₂N₂O₃, 411; Found, 411.

Preparation 66a: 6-(2-fluoro-4-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 54% yield from 2-fluoro-4-methylphenol according to the procedure for Preparation 64a. [M+H] Calc'd for C₁₇H₁₅FO₂, 271; Found, 271.

Preparation 66b: [6-(2-fluoro-4-methylphenoxy)-3,4-dihydronaphthalen-1-yl]methanamine, Hydrochloride

The title compound was prepared in 78% yield from Preparation 66a according to the procedure for Preparation 3a. [M+H] Calc'd for C₁₈H₁₈FNO, 284; Found, 284.

Preparation 66c: [6-(2-fluoro-4-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 92% yield from Preparation 66b according to the procedure for Preparation 3e. [M+H] Calc'd for C₁₈H₂₀FNO, 286; Found, 286.

Preparation 66d: methyl 3-({[(1S)-6-(2-fluoro-4-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 66e: methyl 3-({[(1R)-6-(2-fluoro-4-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 57% yield from Preparation 66c according to the general procedure for Preparation 1e. Separation by chiral HPLC (Column: Chiralcel: IA Sum 4.6*250 mm, Mobile phase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 29% yield of Preparation 66e (6.855 min) and 29% of Preparation 66d (8.064 min), each as a yellow oil. [M+H] Calc'd for C₂₅H₂₅FN₂O₃, 421; Found, 421.

Example 66: 3-({[(1R)-6-(2-fluoro-4-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 83% yield from Preparation 66e according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.64-1.83 (4H, m), 2.32 (3H, s), 2.65-2.69 (2H, m), 3.06-3.09 (1H, m), 3.41-3.47 (1H, m), 3.54-3.59 (1H, m), 6.64 (1H, s), 6.69-6.72 (1H, m), 7.03-7.06 (2H, m), 7.20 (1H, d, J=12.0 Hz), 7.29 (1H, d, J=8.4 Hz), 7.57 (1H, d, J=5.2 Hz), 7.84 (1H, d, J=5.2 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₄H₂₃FN₂O₃, 407; Found, 407.

Preparation 67a: 6-(2-chlorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 64% yield from 2-chlorophenol according to the procedure for Preparation 64a. ¹H NMR (400 MHz, CDCl₃): δ 2.09-2.15 (m, 2H), 2.62 (t, J=6.4 Hz, 2H), 2.90 (t, J=6.0 Hz, 2H), 6.71 (d, J=2.4 Hz, 1H), 6.81 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.11 (dd, J=8.4 Hz, 1.2 Hz, 1H), 7.17-7.22 (m, 1H), 7.28-7.33 (m, 1H), 7.50 (dd, J=8.0 Hz, 1.6 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H). [M+H] Calc'd for C₁₆H₁₃ClO₂, 273; Found, 273.

Preparation 67b: 6-(2-chlorophenoxy)-3,4-dihydronaphthalene-1-carboxamide

The title compound was prepared in 32% yield from Preparation 67a according to the procedure for Preparation 64b. [M+H] Calc'd for C₁₇H₁₄ClNO₂, 300; Found, 300.

Preparation 67c: (1R)-6-(2-chlorophenoxy)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

The title compound was prepared in 52% yield from Preparation 67b according to the procedure for Preparation 64c. [M+H] Calc'd for C₁₇H₁₆ClNO₂, 302; Found, 302.

Preparation 67d: [(1R)-6-(2-chlorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 88% yield from Preparation 67c according to the procedure for Preparation 64d. [M+H] Calc'd for C₁₇H₁₈ClNO, 288; Found, 288.

Preparation 67e: methyl 3-({[(1R)-6-(2-chlorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 31% yield from Preparation 67d according to the procedure for Preparation 64e. [M+H] Calc'd for C₂₄H₂₃ClN₂O₃, 423; Found, 423.

Example 67: 3-({[(1R)-6-(2-chlorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 41% yield from Preparation 67e according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.66-1.70 (m, 1H), 1.78-1.85 (m, 3H), 2.65-2.75 (m, 2H), 3.09-3.13 (m, 1H), 3.41-3.49 (m, 1H), 3.56-3.61 (m, 1H), 670-6.74 (m, 2H), 7.04 (dd, J=8.4 Hz, 0.8 Hz, 1H), 7.18-7.22 (m, 1H), 7.32-7.37 (m, 2H), 7.56 (d, J=5.2 Hz, 1H), 7.59 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.83 (d, J=5.2 Hz, 1H), 8.36 (s, 1H). [M+H] Calc'd for C₂₃H₂₁ClN₂O₃, 409; Found, 409.

Preparation 68a: 6-[(3-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-one

The suspension of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (1.8 g, 6.1 mmol), 3-methylbenzene-1-thiol (0.76 g, 6.1 mmol), Pd₂(dba)₃ (142 mg, 0.153 mmol), Xantphos (177 mg, 0.306 mmol) and DIEA (1.58 g, 12.2 mmol) in 1,4-dioxane (60 mL) was stirred at reflux overnight under N₂. The reaction was filtered and concentrated. Purification by silica gel chromatography (PE:EtOAc=5:1) gave 1.8 g (100%) of the title compound as an orange oil. [M+H] Calc'd for C₁₇H₁₆OS, 269; Found, 269.

Preparation 68b: {6-[(3-methylphenyl)sulfanyl]-3,4-dihydronaphthalen-1-yl}methanamine, Hydrochloride

The title compound was prepared in 69% yield from Preparation 68a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₈H₁₉NS, 282; Found, 282.

Preparation 68c: {6-[(3-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in 92% yield from Preparation 68b according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₈H₂₁NS, 284; Found, 284.

Preparation 68d: methyl 3-({[(1S)-6-[(3-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 69d: methyl 3-({[(1R)-6-[(3-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 25% yield from Preparation 68c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₅H₂₆N₂O₂S, 419; Found, 419.

Separation by chiral HPLC (Column: Chiralcel: IA 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=50:50, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 38% yield of Preparation 68d (6.259 min) and 37% of Preparation 69d (6.802 min), each as a yellow oil.

Example 68: 3-({[(1S)-6-[(3-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 80% yield from Preparation 68d according to the general procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.65-1.85 (4H, m), 2.27 (3H, s), 2.67-2.73 (2H, m), 3.10-3.12 (1H, m), 3.46-3.49 (1H, m), 3.56-3.57 (1H, m), 7.05-7.15 (5H, m), 7.22-7.27 (1H, m), 7.32-7.35 (1H, m), 7.55 (1H, d, J=5.1 Hz), 7.83-7.84 (1H, m), 8.35 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₂S, 405; Found, 405.

Example 69: 3-({[(1R)-6-[(3-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 83% yield from Preparation 69d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.65-1.85 (4H, m), 2.27 (3H, s), 2.67-2.71 (2H, m), 3.09-3.14 (1H, m), 3.46-3.50 (1H, m), 3.56-3.57 (1H, m), 7.05-7.15 (5H, m), 7.22-7.27 (1H, m), 7.33 (1H, d, J=7.8 Hz), 7.55 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=4.8 Hz), 8.36 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₂S, 405; Found, 405.

Preparation 70a: 6-[(2-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 92% yield from 3-methylbenzene-1-thiol according to the general procedure for Preparation 68a. [M+H] Calc'd for C₁₇H₁₆OS, 269; Found, 269.

Preparation 70b: {6-[(2-methylphenyl)sulfanyl]-3,4-dihydronaphthalen-1-yl}methanamine, Hydrochloride

The title compound was prepared in 89% yield from Preparation 68a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₈H₁₉NS, 282; Found, 282.

Preparation 70c: {6-[(2-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in 88% yield from Preparation 70b according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₈H₂₁NS, 284; Found, 284.

Preparation 70d: methyl 3-({[(1S)-6-[(2-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 70d: methyl 3-({[(1R)-6-[(2-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (550 mg) of the title compounds was prepared in 37% yield from Preparation 70c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₅H₂₆N₂O₂S, 419; Found, 419.

Separation by chiral HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) 160 mg (11%) of Preparation 70d (6.645 min) and 150 mg (10%) of Preparation 71d (7.659 min), each as a yellow oil.

Example 70: 3-({[(1S)-6-[(2-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 84% yield from Preparation 70d according to the general procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.64-1.68 (1H, m), 1.77-1.84 (3H, m), 2.31 (3H, s), 2.67-2.70 (2H, m), 3.08-3.12 (1H, m), 3.42-3.49 (1H, m), 3.55-3.60 (1H, m), 6.95 (1H, d, J=7.8 Hz), 7.02 (1H, s), 7.12-7.25 (3H, m), 7.29-7.33 (2H, m), 7.55 (1H, d, J=5.1 Hz), 7.83 (1H, d, J=5.1 Hz), 8.35 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₂S, 405; Found, 405.

Example 71: 3-({[(1R)-6-[(2-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 93% yield from Preparation 71d according to the general procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.64-1.68 (1H, m), 1.77-1.84 (3H, m), 2.31 (3H, s), 2.67-2.70 (2H, m), 3.08-3.12 (1H, m), 3.42-3.49 (1H, m), 3.55-3.60 (1H, m), 6.95 (1H, d, J=7.8 Hz), 7.02 (1H, s), 7.12-7.25 (3H, m), 7.29-7.33 (2H, m), 7.55 (1H, d, J=5.1 Hz), 7.83 (1H, d, J=5.1 Hz), 8.35 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₂S, 405; Found, 405.

Preparation 72a: 6-[(2-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-one

To a suspension of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl 4-methylbenzene-1-sulfonate (3.0 g, 10.2 mmol), 2,2′-difluorodiphenyldisulfide (1.0 mL, 5.1 mmol) and Zn (800 mg, 12.2 mmol) in THF (30 mL) was added Pd(dppf)Cl₂ (374 mg, 0.51 mmol) at rt under N₂. The reaction was stirred at reflux overnight. The reaction was filtered and concentrated. Purification by silica gel chromatography (PE:EtOAc=30:1 to 10:1) gave 2.4 g (86%) of the title compound as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 2.07-2.13 (m, 2H), 2.62 (t, J=6.4 Hz, 2H), 2.87 (t, J=6.0 Hz, 2H), 7.01-7.03 (m, 2H), 7.17-7.21 (m, 2H), 7.40-7.46 (m, 1H), 7.51 (dt, J=8.0 Hz, 1.2 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H). [M+H] Calc'd for C₁₆H₁₃FOS, 273; Found, 273.

Preparation 72b: {6-[(2-fluorophenyl)sulfanyl]-3,4-dihydronaphthalen-1-yl}methanamine, Hydrochloride

The title compound was prepared in 80% yield from Preparation 72a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₇H₁₆FNS, 286; Found, 286.

Preparation 72c: {6-[(2-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in 71% yield from Preparation 72b according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₇H₁₈FNS, 288; Found, 288.

Preparation 72d: methyl 3-({[(1S)-6-[(2-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 73d: methyl 3-({[(1R)-6-[(2-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (410 mg) of the title compounds was prepared in 28% yield from Preparation 72c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₄H₂₃FN₂O₂S, 423; Found, 423.

Separation by chiral HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 115 mg (28%) of Preparation 71d (7.352 min) and 114 mg (28%) of Preparation 72d (8.388 min), each as a colorless oil.

Example 72: 3-({[(1S)-6-[(2-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 88% yield from Preparation 72d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.64-1.70 (m, 1H), 1.76-1.86 (m, 3H), 2.65-2.76 (m, 2H), 3.09-3.15 (m, 1H), 3.44-3.49 (m, 1H), 3.57-3.61 (m, 1H), 7.06-7.09 (m, 1H), 7.12 (s, 1H), 7.20-7.22 (m, 2H), 7.28-7.39 (m, 3H), 7.55 (d, J=4.8 Hz, 1H), 7.83 (d, J=4.8 Hz, 1H), 8.36 (s, 1H). [M+H] Calc'd for C₂₃H₂₁FN₂O₂S, 409; Found, 409.

Example 73: 3-({[(1R)-6-[(2-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 50% yield from Preparation 73d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.64-1.69 (m, 1H), 1.78-1.85 (m, 3H), 2.65-2.76 (m, 2H), 3.10-3.14 (m, 1H), 3.44-3.50 (m, 1H), 3.57-3.61 (m, 1H), 7.07-7.09 (m, 1H), 7.12 (s, 1H), 7.18-7.24 (m, 2H), 7.28-7.41 (m, 3H), 7.55 (d, J=4.8 Hz, 1H), 7.83 (d, J=4.8 Hz, 1H), 8.36 (s, 1H). [M+H] Calc'd for C₂₃H₂₁FN₂O₂S, 409; Found, 409.

Preparation 74a: 6-[(3-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 76% yield from 3,3′-difluorodiphenyldisulfide according to the general procedure for Preparation 72a. [M+H] Calc'd for C₁₆H₁₃FOS, 273; Found, 273.

Preparation 74b: {6-[(3-fluorophenyl)sulfanyl]-3,4-dihydronaphthalen-1-yl}methanamine, Hydrochloride

The title compound was prepared in 54% yield from Preparation 74a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₇H₁₆FNS, 286; Found, 286.

Preparation 74c: {6-[(3-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in 75% yield from Preparation 74b according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₇H₁₈FNS, 288; Found, 288.

Preparation 74d: methyl 3-({[(1S)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 75d: methyl 3-({[(1R)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (600 mg) of the title compounds was prepared in 43% yield from Preparation 74c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₄H₂₃FN₂O₂S, 423; Found, 423.

Separation by chiral HPLC (Column: Chiralcel: OD-H 5 um 4.6*250 mm, Mobile phase: Hex: EtOH:DEA=70:30:0.2, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 80 mg (13%) of Preparation 74d (6.571 min) and 70 mg (12%) of Preparation 75d (7.213 min), each as a yellow oil.

Example 74: 3-({[(1S)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 64% yield from Preparation 74d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.67-1.69 (1H, m), 1.79-1.83 (3H, m), 2.68-2.75 (2H, m), 3.10-3.12 (1H, m), 3.36-3.42 (1H, m), 3.53-3.58 (1H, m), 7.01-7.08 (3H, m), 7.19-7.22 (2H, m), 7.35-7.42 (2H, m), 7.57 (1H, d, J=4.4 Hz), 7.78 (1H, d, J=4.8 Hz), 8.23 (1H, s). [M+H] Calc'd for C₂₃H₂₁FN₂O₂S, 409; Found, 409.

Example 75: 3-({[(1R)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 74% yield from Preparation 75d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.67-1.69 (1H, m), 1.79-1.83 (3H, m), 2.68-2.75 (2H, m), 3.10-3.12 (1H, m), 3.36-3.42 (1H, m), 3.53-3.58 (1H, m), 7.01-7.08 (3H, m), 7.19-7.22 (2H, m), 7.35-7.42 (2H, m), 7.57 (1H, d, J=4.4 Hz), 7.78 (1H, d, J=4.8 Hz), 8.23 (1H, s). [M+H] Calc'd for C₂₃H₂₁FN₂O₂S, 409; Found, 409.

Preparation 76a: 6-[(4-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl 4-methylbenzene-1-sulfonate (5.0 g, 17.0 mmol) in dioxane (75 mL) was added 4-fluorothiophenol (2.6 g, 20.4 mmol), Pd₂(dba)₃ (392 mg, 0.43 mmol), Xantphos (492 mg, 0.85 mmol) and DIEA (4.4 g, 34.0 mmol). The mixture was heated to reflux overnight under nitrogen. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=20:1 to 5:1) to give 3.6 g (77%) of the title compound as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 2.08-2.13 (m, 2H), 2.61 (t, J=6.4 Hz, 2H), 2.85 (t, J=6.0 Hz, 2H), 6.94 (br s, 1H), 6.98 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.10-7.14 (m, 2H), 7.49-7.53 (m, 2H), 7.88 (d, J=8.4 Hz, 1H). [M+H] Calc'd for C₁₆H₁₃FOS, 273; Found, 273.

Preparation 76b: {6-[(4-fluorophenyl)sulfanyl]-3,4-dihydronaphthalen-1-yl}methanamine, Hydrochloride

The title compound was prepared in 69% yield from Preparation 76a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₇H₁₆FNS, 286; Found, 286.

Preparation 76c: {6-[(4-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in 97% yield from Preparation 76b according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₇H₁₈FNS, 288; Found, 288.

Preparation 76d: methyl 3-({[(1S)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 77d: methyl 3-({[(1R)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (330 mg) of the title compounds was prepared in 20% yield from Preparation 76c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₄H₂₃FN₂O₂S, 423; Found, 423.

Separation by chiral HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 84 mg (25%) of Preparation 76d (6.916 min) and 91 mg (28%) of Preparation 77d (7.681 min), each as a colorless oil.

Example 76: 3-({[(1S)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 48% yield from Preparation 76d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.65-1.68 (m, 1H), 1.78-1.83 (m, 3H), 2.64-2.75 (m, 2H), 3.18-3.12 (m, 1H), 3.43-3.48 (m, 1H), 3.56-3.62 (m, 1H), 7.04-7.07 (m, 1H), 7.09 (s, 1H), 7.21-7.25 (m, 2H), 7.32-7.39 (m, 3H), 7.55 (d, J=5.2 Hz, 1H), 7.83 (d, J=5.2 Hz, 1H), 8.35 (s, 1H). [M+H] Calc'd for C₂₃H₂₁FN₂O₂S, 409; Found, 409.

Example 77: 3-({[(1R)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 57% yield from Preparation 77d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.64-1.69 (m, 1H), 1.77-1.84 (m, 3H), 2.65-2.75 (m, 2H), 3.07-3.12 (m, 1H), 3.42-3.48 (m, 1H), 3.56-3.60 (m, 1H), 7.04-7.06 (m, 1H), 7.09 (s, 1H), 7.21-7.25 (m, 2H), 7.32-7.39 (m, 3H), 7.55 (d, J=5.2 Hz, 1H), 7.83 (d, J=5.2 Hz, 1H), 8.35 (s, 1H). [M+H] Calc'd for C₂₃H₂₁FN₂O₂S, 409; Found, 409.

Preparation 78a: 6-[(4-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 96% yield from 4-tolyl disulfide according to the general procedure for Preparation 72a. [M+H] Calc'd for C₁₇H₁₆OS, 269; Found, 269.

Preparation 78b: {6-[(4-methylphenyl)sulfanyl]-3,4-dihydronaphthalen-1-yl}methanamine, Hydrochloride

The title compound was prepared in 77% yield from Preparation 76a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₈H₁₉NS, 282; Found, 282.

Preparation 78c: {6-[(4-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in 68% yield from Preparation 78b according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₈H₂₁NS, 284; Found, 284.

Preparation 78d: methyl 3-({[(1S)-6-[(4-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 79d: methyl 3-({[(1R)-6-[(4-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (200 mg) of the title compounds was prepared in 20% yield from Preparation 78c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₅H₂₆N₂O₂S, 419; Found, 419.

Separation by chiral HPLC (Column: Chiralcel IC, 250 mm*4.6 mm 5 um; Mobile phase: Hex:EtOH=80:20; F: 1.0 mL/min; W: 230 nm; T=30° C.) gave 66 mg (33%) of Preparation 78d (9.08 min) and 66 mg (33%) of Preparation 79d (10.33 min), each as a yellow oil.

Example 78: 3-({[(1S)-6-[(4-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 40% yield from Preparation 78d according to the general procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.62-1.67 (1H, m), 1.75-1.85 (3H, m), 2.29 (3H, s), 2.64-2.71 (2H, m), 3.06-3.11 (1H, m), 3.41-3.48 (1H, m), 3.54-3.60 (1H, m), 6.99-7.04 (2H, m), 7.17-7.31 (5H, m), 7.55 (1H, d, J=5.1 Hz), 7.82 (1H, d, J=5.1 Hz), 8.35 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₂S, 405; Found, 405.

Example 79: 3-({[(1R)-6-[(4-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 40% yield from Preparation 79d according to the general procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.63-1.67 (1H, m), 1.76-1.85 (3H, m), 2.29 (3H, s), 2.64-2.68 (2H, m), 3.07-3.10 (1H, m), 3.40-3.47 (1H, m), 3.53-3.59 (1H, m), 6.99-7.04 (2H, m), 7.17-7.31 (5H, m), 7.54 (1H, d, J=5.1 Hz), 7.82 (1H, d, J=4.8 Hz), 8.34 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₂S, 405; Found, 405.

Preparation 80a: 6-bromo-1,2,3,4-tetrahydronaphthalen-1-ol

To a solution of of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (2.0 g, 8.9 mmol) in EtOH (20 mL) was added NaBH₄ (1.6 g, 42.7 mmol) at rt, and the reaction was stirred for 30 min. The reaction was diluted with water (10 mL) and extracted with EtOAc (3×50 mL). Organics were washed with brine (50 mL), dried (Na₂SO₄) and concentrated to give 1.9 g (94%) of the title compound as a brown oil. [M+H] calc'd for C₁₀H₁₁BrO₂, 227, 229; found 227, 229.

Preparation 80b: triethyl (6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)methanetricarboxylate

To a solution of Preparation 80a (1.83 g, 8.1 mmol) and triethylmethane tricarboxylate (3.76 g, 16.2 mmol) in toluene (20 mL) was added n-Bu₃P (4.0 mL, 16.2 mmol), and the solution was cooled to −50° C. under N₂. DIAD (3.2 mL, 16.2 mmol) was added dropwise, and the reaction mixture stirred for 30 min. The reaction was concentrated. Water (50 mL) and 3N NaOH (50 mL) were added, and the solution was extracted with ether. Organics were washed with 3N NaOH, water, 1N HCl, and brine. The solution was dried (Na₂SO₄) and concentrated. Purification by silica gel chromatography (10% EtOAc/hexanes) gave 2.84 g (79%) of the title compound as a white solid. [M+H] calc'd for C₂₀H₂₅BrO₆, 441, 443; found 441, 443.

Preparation 80c: 2-(6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)acetic Acid

To a solution of Preparation 80b (2.84 g, 6.4 mmol) in methanol (10 mL) was added 1.5 N NaOH (50 mL) at rt, and the mixture was refluxed for 20 h. The reaction mixture was concentrated. Glacial acetic acid (50 mL) was added, and the reaction was refluxed for 3 h. The reaction mixture was concentrated and the residue was taken up in water and extracted with ether. Organics were dried (Na₂SO₄) and concentrated to give 1.58 g (91%) of the title compound as a yellow oil. [M+H] calc'd for C₁₂H₁₃BrO₂, 269, 271; found 269, 271.

Preparation 80d: (6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

To a solution of Preparation 80c (0.8 g, 3.0 mmol) in DCM (20 mL) was added oxalyl chloride (0.4 mL, 4.5 mmol) and DMF (5 drops) at rt, and the mixture was stirred for 1 h. The solvent was removed in vacuo, and the residue was dissolved in acetone (20 mL). A solution of NaN₃ (390 mg, 6.0 mmol) in H₂O (3 mL) was added slowly at 0° C. After 10 min, the mixture was diluted with water and brine, and extracted with toluene. Organics were washed with brine, dried (Na₂SO₄), and then heated to reflux for 30 min. The solution was concentrated and re-dissolved in dioxane (10 mL). The solution was added dropwise to conc. HCl (20 mL) at 100° C. After 20 min, the reaction mixture was concentrated. The residue was dissolved in DCM/MeOH (1:1), basified to pH 8 with sat. Na₂CO₃, filtered, and concentrated to give the title compound as pale brown oil which was used for next reaction without further purification. [M+H] calc'd for C₁₁H₁₄BrN, 240, 242; found 240, 242.

Preparation 80e: methyl 3-{[(7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 6% yield from Preparation 80d according to the procedure for Preparation 1e. [M+H] calc'd for C₁₈H₁₉BrN₂O₂, 375, 377; found 375, 377.

Example 80: 3-({[6-(pyridin-2-ylsulfanyl) 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

To a suspension of Preparation 80e (72 mg, 0.19 mmol), 2,2′-dipyridyl disulfide (84 mg, 0.38 mmol) and Zn (60 mg, 0.91 mmol) in DMF (5 mL) was added Pd(dppf)Cl₂ (30 mg, 0.038 mmol) at rt under N₂, and the reaction was stirred at 60° C. overnight. The reaction was diluted with EtOAc, filtered, and concentrated. The residue was purified by prep-TLC (PE:EA=2:1) to give a pale brown oil. This oil was dissolved in THF (3 mL) and H₂O (1 mL). LiOH.H₂O (2 mg) was added, and the reaction was stirred at rt for 2 h. The reaction mixture was acidified to pH=3 with 1.0 N aqueous HCl solution, concentrated and purified by prep-HPLC to give 4.8 mg (6%) of the title compound as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ 1.81-1.86 (m, 1H), 1.91-2.08 (m, 3H), 2.86-2.91 (m, 2H), 3.35-3.38 (m, 1H), 3.65-3.73 (m, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.49-7.55 (m, 3H), 7.98 (d, J=6.0 Hz, 1H), 8.06 (t, J=7.6 Hz, 1H), 8.31 (d, J=6.0 Hz, 1H), 8.44 (s, 1H), 8.55 (d, J=5.6 Hz, 1H). [M+H] Calc'd for C₂₂H₂₁N₃O₂S, 392; Found, 392.

Preparation 81a: 6-(phenylsulfanyl)-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl 4-methylbenzene-1-sulfonate (8.83 g, 30 mmol) and diphenyl disulphide (3.27 g, 15 mmol) in THF (20 mL) was added Zn powder (2.34 g, 36 mmol) and Pd(dppf)Cl₂ (1.22 g, 1.5 mmol) under nitrogen, and the reaction was refluxed overnight. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography to give 5.93 g (77%) of the title compound as an orange solid. ¹H NMR (400 MHz, CDCl₃): δ 2.06-2.12 (2H, m), 2.61 (2H, t, J=6.6 Hz), 2.85 (2H, t, J=6.0 Hz), 7.01-7.04 (2H, m), 7.39-7.42 (3H, m), 7.49-7.51 (2H, m), 7.89 (1H, d, J=8.0 Hz). [M+H] Calc'd for C₁₆H₁₄OS, 255; Found, 255.

Preparation 81b: 6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of Preparation 81a (1.72 g, 6.77 mmol) in MeOH/MeCN (1:1, 30 mL) was added another solution of OXONE (16.6 g, 27 mmol) in water. The mixture was stirred for 2 h at rt. The reaction was diluted with EtOAc and filtered, washed with brine, dried (Na₂SO₄), and concentrated to give 1.9 g (98%) of the title compound as colorless gum. [M+H] Calc'd for C₁₆H₁₄O₃S, 287; Found, 287.

Preparation 81c: [6-(benzenesulfonyl)-3,4-dihydronaphthalen-1-yl]methanamine

The title compound was prepared in 31% yield from Preparation 81b according to the procedure for Preparation 3a. [M+H] Calc'd for C₁₇H₁₇NO₂S, 300; Found, 300.

Preparation 81d: [6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 91% yield from Preparation 81c according to the procedure for Preparation 3e. [M+H] Calc'd for C₁₇H₁₉NO₂S, 302; Found, 302.

Preparation 81e: methyl 3-({[6-(benzenesulfonyl)-3,4-dihydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 43% yield from Preparation 81d according to the procedure for Preparation 1e. [M+H] Calc'd for C₂₄H₂₄N₂O₄S, 437; Found, 437.

Preparation 81f: methyl 3-({[(1S)-6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 82f: methyl 3-({[(1R)-6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

Preparation 81e (360 mg) was separated by chiral HPLC (Column: Chiralcel AS-H, 250 mm*4.6 mm 5 um; Mobile phase: Hex:EtOH=50:50; F: 1.0 mL/min; W: 230 nm; T=30° C.) to give 116 mg (32%) of Preparation 81e (10.39 min) and 107 mg (30%) of Preparation 82e (20.88 min), each as a yellow oil.

Example 81: 3-({[(1S)-6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 81% yield from Preparation 81f according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.66-1.70 (1H, m), 1.77-1.86 (3H, m), 2.75-2.88 (2H, m), 3.18-3.19 (1H, m), 3.44-3.50 (1H, m), 3.56-3.61 (1H, m), 7.55-7.71 (7H, m), 7.86 (1H, d, J=5.6 Hz), 7.94 (2H, d, J=7.2 Hz), 8.41 (1H, s). [M+H] Calc'd for C₂₃H₂₂N₂O₄S, 423; Found, 423.

Example 82: 3-({[(1R)-6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 90% yield from Preparation 82f according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.66-1.70 (1H, m), 1.77-1.85 (3H, m), 2.78-2.83 (2H, m), 3.18-3.21 (1H, m), 3.45-3.51 (1H, m), 3.57-3.61 (1H, m), 7.55-7.76 (7H, m), 7.89 (1H, d, J=5.2 Hz), 7.94 (2H, d, J=7.2 Hz), 8.42 (1H, s). [M+H] Calc'd for C₂₃H₂₂N₂O₄S, 423; Found, 423.

Preparation 83a: 6-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 97% yield from Preparation 78a according to the general procedure for Preparation 81b. [M+H] Calc'd for C₁₇H₁₆O₃S, 301; Found, 301.

Preparation 83b: [6-(4-methylbenzenesulfonyl)-3,4-dihydronaphthalen-1-yl]methanamine, Hydrochloride

The title compound was prepared in 60% yield from Preparation 83a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₈H₁₉NO₂S, 314; Found, 314.

Preparation 83c: [6-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 78% yield from Preparation 83b according to the procedure for Preparation 3e. [M+H] Calc'd for C₁₈H₂₁NO₂S, 316; Found, 316.

Preparation 83d: methyl 3-({[(1S)-6-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 84d: methyl 3-({[(1R)-6-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (226 mg) of the title compounds was prepared in 24% yield from Preparation 83c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₅H₂₆N₂O₄S, 451; Found, 451.

Separation by chiral HPLC (Column: Chiralcel AS-H, 250 mm*4.6 mm 5 um; Mobile phase: MeOH:EtOH=50:50; F: 1.0 mL/min; W: 230 nm; T=30° C.) gave 95 mg (42%) of Preparation 83d (9.67 min), and 86 mg (38%) of Preparation 84d (16.75 min), each as colorless oil.

Example 83: 3-({[(1S)-6-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 56% yield from Preparation 83d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.66-1.69 (1H, m), 1.76-1.84 (3H, m), 2.35 (3H, s), 2.76-2.83 (2H, m), 3.15-3.18 (1H, m), 3.35-3.48 (1H, m), 3.55-3.60 (1H, m), 7.40 (2H, d, J=8.4 Hz), 7.53-7.57 (2H, m), 7.62-7.67 (2H, m), 7.81-7.84 (3H, m), 8.37 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₄S, 437; Found, 437.

Example 84: 3-({[(1R)-6-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 63% yield from Preparation 84d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.65-1.69 (1H, m), 1.76-1.86 (3H, m), 2.36 (3H, s), 2.76-2.86 (2H, m), 3.15-3.18 (1H, m), 3.35-3.48 (1H, m), 3.55-3.60 (1H, m), 7.40 (2H, d, J=8.0 Hz), 7.53-7.57 (2H, m), 7.62-7.67 (2H, m), 7.81-7.84 (3H, m), 8.37 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₄S, 437; Found, 437.

Preparation 85a: 6-(3-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 84% yield from Preparation 68a according to the general procedure for Preparation 81b. [M+H] Calc'd for C₁₇H₁₆O₃S, 301; Found, 301.

Preparation 85b: [6-(3-methylbenzenesulfonyl)-3,4-dihydronaphthalen-1-yl]methanamine, Hydrochloride

The title compound was prepared in 95% yield from Preparation 85a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₈H₁₉NO₂S, 314; Found, 314.

Preparation 85c: [6-(3-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 64% yield from Preparation 85b according to the procedure for Preparation 3e. [M+H] Calc'd for C₁₈H₂₁NO₂S, 316; Found, 316.

Preparation 85d: methyl 3-({[(1S)-6-(3-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 86d: methyl 3-({[(1R)-6-(3-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (230 mg) of the title compounds was prepared in 16% yield from Preparation 85c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₅H₂₆N₂O₄S, 451; Found, 451.

Separation by chiral HPLC (Column: Chiralcel: AS 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=50:50, F: 1.0 mL/min, W: 230 nm, T: 30° C.) to give 77 mg (33%) of Preparation 85d (9.653 min) and 77 mg (33%) of Preparation 86d (15.046 min), each as a yellow oil.

Example 85: 3-({[(1S)-6-(3-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 95% yield from Preparation 85d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.65-1.87 (4H, m), 2.38 (3H, s), 2.76-2.88 (2H, m), 3.18-3.21 (1H, m), 3.46-3.51 (1H, m), 3.58-3.63 (1H, m), 7.49-7.58 (3H, m), 7.66-7.85 (5H, m), 7.89 (1H, d, J=5.2 Hz), 8.44 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₄S, 437; Found, 437.

Example 86: 3-({[(1R)-6-(3-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 78% yield from Preparation 86d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.67-1.83 (4H, m), 2.38 (3H, s), 2.78-2.88 (2H, m), 3.18-3.21 (1H, m), 3.45-3.50 (1H, m), 3.57-3.62 (1H, m), 7.49-7.57 (3H, m), 7.66-7.83 (5H, m), 7.88 (1H, d, J=5.2 Hz), 8.42 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₄S, 437; Found, 437.

Preparation 87a: 6-(3-fluorobenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 40% yield from Preparation 74a according to the general procedure for Preparation 81b. [M+H] Calc'd for C₁₆H₁₃FO₃S, 305; Found, 305.

Preparation 87b: [6-(3-fluorobenzenesulfonyl)-3,4-dihydronaphthalen-1-yl]methanamine, Hydrochloride

The title compound was prepared in 87% yield from Preparation 87a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₇H₁₆FNO₂S, 318; Found, 318.

Preparation 87c: [6-(3-fluorobenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 73% yield from Preparation 87b according to the procedure for Preparation 3e. [M+H] Calc'd for C₁₇H₁₈FNO₂S, 320; Found, 320.

Preparation 87d: methyl 3-({[6-(3-fluorobenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 6% yield from Preparation 87c according to the procedure for Preparation 1e. [M+H] Calc'd for C₂₄H₂₃FN₂O₄S, 455; Found, 455.

Example 87: 3-({[6-(3-fluorobenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 73% yield from Preparation 87d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.67-1.86 (4H, m), 2.78-2.85 (2H, m), 3.18-3.22 (1H, m), 3.45-3.51 (1H, m), 3.57-3.62 (1H, m), 7.54-7.59 (2H, m), 7.65-7.87 (8H, m), 8.40 (1H, s). [M+H] Calc'd for C₂₃H₂₁FN₂O₄S, 441; Found, 441.

Preparation 88a: 6-(3,6-dihydro-2H-pyran-4-yl)-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (1.4 g, 4.76 mmol) in dioxane (6 mL) was added 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.0 g, 4.76 mmol), Pd(dppf)Cl₂DCM (408 mg, 0.5 mmol) and sat. NaHCO₃ solution (2 mL). The mixture was stirred at 100° C. for 2 h under nitrogen. The mixture was cooled to rt and diluted with EtOAc, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=4:1) to give 930 mg (86%) of the title compound as yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 2.13-2.16 (2H, m), 2.53 (2H, s), 2.65 (2H, t, J=6.4 Hz), 2.96 (2H, t, J=6.0 Hz), 3.94 (2H, t, J=5.6 Hz), 4.34 (2H, s), 6.26 (1H, s), 7.25 (1H, d, J=5.6 Hz), 7.33 (1H, d, J=8.4 Hz), 7.99 (1H, d, J=8.0 Hz). [M+H] Calc'd for C₁₅H₁₆O₂, 229; Found, 229.

Preparation 88b: [6-(oxan-4-yl)-3,4-dihydronaphthalen-1-yl]methanamine

The title compound was prepared in 40% yield from Preparation 88a according to the procedure for Preparation 3a. [M+H] Calc'd for C₁₆H₂₁NO, 244; Found, 244.

Preparation 88c: [6-(oxan-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 86% yield from Preparation 88b according to the procedure for Preparation 3e. [M+H] Calc'd for C₁₆H₂₃NO, 246; Found, 246.

Preparation 88d: methyl 3-({[6-(oxan-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 17% yield from Preparation 88c according to the procedure for Preparation 1e. [M+H] Calc'd for C₂₃H₂₈N₂O₃, 381; Found, 381.

Example 88: 3-({[6-(oxan-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 69% yield from Preparation 88d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.61-1.68 (5H, m), 1.77-1.83 (3H, m), 2.65-2.72 (3H, m), 3.04-3.07 (1H, m), 3.37-3.45 (3H, m), 3.54-3.59 (1H, m), 3.91-3.94 (2H, m), 6.96 (1H, s), 7.00 (1H, d, J=8.4 Hz), 7.24 (1H, d, J=8.0 Hz), 7.56 (1H, d, J=5.2 Hz), 7.83 (1H, d, J=5.2 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₂H₂₆N₂O₃, 367; Found, 367.

Preparation 89a: 6-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-one

To a suspension of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl 4-methylbenzene-1-sulfonate (1.3 g, 4.4 mmol), 2-methylpyridine-4-boronic acid pinacol ester (800 mg, 3.7 mmol), Na₂CO₃ (773 mg, 7.3 mmol) and LiCl.H₂O (442 mg, 7.3 mmol) in EtOH/H₂O/toluene (4.4 mL/2.3 mL/20.0 mL) was added Pd(PPh₃)₄ (211 mg, 0.2 mmol) at rt under N₂. The reaction was stirred at 100° C. overnight. The reaction was filtered and concentrated. Purification by silica gel chromatography (PE:EtOAc=1:1) gave 865 mg (quantitative) of the title compound as a yellow solid. [M+H] Calc'd for C₁₆H₁₅NO, 238; Found, 238.

Preparation 89b: [6-(2-methylpyridin-4-yl)-3,4-dihydronaphthalen-1-yl]methanamine, Hydrochloride

The title compound was prepared in 44% yield from Preparation 89a according to the procedure for Preparation 3a. [M+H] Calc'd for C₁₇H₁₈N, 251; Found, 251.

Preparation 89c: [6-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 98% yield from Preparation 89b according to the procedure for Preparation 3e. [M+H] Calc'd for C₁₇H₂₀N, 253; Found, 253.

Preparation 89d: methyl 3-({[6-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 5% yield from Preparation 88c according to the procedure for Preparation 1e. [M+H] Calc'd for C₂₄H₂₅N₃O₂, 388; Found, 388.

Example 89: 3-({[6-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid, Hydrochloride

The title compound was prepared in 40% yield from Preparation 89d according to the general procedure for Example 1, and the product was purified by prep-HPLC. ¹H NMR (400 MHz, DMSO-d₆): δ 1.75-1.92 (4H, m), 2.78 (3H, s), 2.85-2.89 (2H, m), 3.25-3.29 (1H, m), 3.55-3.60 (1H, m), 3.68-3.73 (1H, m), 7.59 (1H, d, J=8.0 Hz), 7.80-7.82 (2H, m), 7.95-7.97 (2H, m), 8.07 (1H, brs), 8.20-8.22 (1H, m), 8.33 (1H, s), 8.54 (1H, s), 8.78 (1H, d, J=6.4 Hz). [M+H] Calc'd for C₂₃H₂₃N₃O₂, 374; Found, 374.

Preparation 90a: tert-butyl N-[(6-ethenyl-3,4-dihydronaphthalen-1-yl)methyl]carbamate

To a solution of Preparation 3b (1.0 g, 2.97 mmol) in DMSO (20 mL) was added potassium vinyltrifluoroborate (600 mg, 4.45 mmol), K₂CO₃ (820 mg, 5.94 mmol) and Pd(dppf)Cl₂ (74 mg, 0.09 mmol). The mixture was stirred at 80° C. for 2 h under nitrogen. The mixture was poured into water and extracted with EtOAc. Organics were washed with brine, dried (Na₂SO₄), and concentrated. The residue was purified by HPLC to give 700 mg (82%) of the title compound as white solid. ¹H NMR (400 MHz, CDCl₃): δ 1.48 (9H, s), 2.26-2.32 (2H, m), 2.75 (2H, t, J=8.0 Hz), 4.14 (2H, d, J=4.8 Hz), 4.57 (1H, s), 5.20 (1H, d, J=11.2 Hz), 5.71 (1H, d, J=17.6 Hz), 6.00-6.02 (1H, m), 6.63-6.71 (1H, m), 7.19-7.24 (2H, m). [M+H] Calc'd for C₁₈H₂₃NO₂, 286; Found, 286.

Preparation 90b: (6-ethenyl-3,4-dihydronaphthalen-1-yl)methanamine, Hydrochloride

A mixture of Preparation 90a (700 mg, 2.45 mmol) in 6N HCl/EA solution (10 mL) was stirred overnight at rt. The reaction mixture was concentrated to give 400 mg (88%) of the title compound as a yellow solid. [M+H] Calc'd for C₁₃H₁₅N, 186; Found, 186.

Preparation 90c: (6-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in 98% yield from Preparation 88b according to the procedure for Preparation 3e. [M+H] Calc'd for C₁₃H₁₉N, 190; Found, 190.

Preparation 90d: methyl 3-{[(6-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 90c according to the procedure for Preparation 1e. [M+H] Calc'd for C₂₀H₂₄N₂O₂, 325; Found, 325.

Preparation 90e: methyl 3-({[(1S)-6-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 91e: methyl 3-({[(1R)-6-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

Preparation 90d (146 mg) was separated by chiral HPLC (Column: Chiralcel OJ, 250 mm*4.6 mm Sum; Mobile phase: 70:30 CO₂:MeOH; F: 1.0 mL/min; W: 230 nm; T=30° C.) to give 56 mg (38%) of Preparation 91e (2.16 min) and 53 mg (36%) of Preparation 90e (2.88 min), each as a yellow gum.

Example 90: 3-({[(1S)-6-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 58% yield from Preparation 90e according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.15 (3H, t, J=7.6 Hz), 1.64-1.68 (1H, m), 1.77-1.83 (3H, m), 2.53-2.55 (2H, m), 2.67-2.71 (2H, m), 3.04-3.07 (1H, m), 3.39-3.44 (1H, m), 3.53-3.57 (1H, m), 6.92 (1H, s), 6.95 (1H, d, J=7.6 Hz), 7.20 (1H, d, J=8.0 Hz), 7.55 (1H, d, J=5.2 Hz), 7.82 (1H, d, J=4.0 Hz), 8.35 (1H, s). [M+H] Calc'd for C₁₉H₂₂N₂O₂, 311; Found, 311.

Example 91: 3-({[(1R)-6-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 72% yield from Preparation 91e according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.15 (3H, t, J=7.6 Hz), 1.63-1.69 (1H, m), 1.77-1.87 (3H, m), 2.53-2.55 (2H, m), 2.65-2.75 (2H, m), 3.04-3.07 (1H, m), 3.38-3.45 (1H, m), 3.53-3.57 (1H, m), 6.92 (1H, s), 6.95 (1H, d, J=7.2 Hz), 7.20 (1H, d, J=7.6 Hz), 7.55 (1H, d, J=5.2 Hz), 7.82 (1H, d, J=4.0 Hz), 8.36 (1H, s). [M+H] Calc'd for C₁₉H₂₂N₂O₂, 311; Found, 311.

Preparation 92a: 4-(2,3-dihydro-1-benzofuran-7-yl)but-3-enoic Acid

To a solution of (2-carboxyethyl)triphenylphosphonium bromide (617 mg, 1.5 mmol) in THF (20 mL) was added NaHMDS (1.5 mL, 3.0 mmol) at −20° C., and the reaction was stirred for 20 min. 2,3-Dihydro-1-benzofuran-7-carbaldehyde (200 mg, 1.4 mmol) was added to the reaction at −78° C., and the reaction was stirred overnight while warming to rt. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). Organics were washed with brine (30 mL), dried (Na₂SO₄), and concentrated to give the crude title compound as a yellow solid. [M+H] Calc'd for C₁₂H₁₂O₃, 205; Found, 205.

Preparation 92b: 4-(2,3-dihydro-1-benzofuran-7-yl)butanoic Acid

To a solution of Preparation 92a (6.8 mmol) in MeOH (30 mL) was added 10% Pd/C (200 mg) at rt under N₂. The mixture was stirred at rt overnight with 50 psi H₂. The reaction was filtered through Celite and concentrated to give 1.2 g (86%) of the crude title compound as a yellow oil. [M+H] Calc'd for C₁₂H₁₄O₃, 207; Found, 207.

Preparation 92c: 2H,3H,6H,7H,8H,9H-naphtho[1,2-b]furan-6-one

PPA (5 mL) was added to Preparation 92b (1.2 g, 5.8 mmol) at rt, and the reaction was stirred at 95° C. for 1.5 h. The solution was poured into water (50 mL) at rt, extracted with EtOAc (3×50 mL), washed with brine (50 mL), dried (Na₂SO₄), and concentrated. Purification by silica gel chromatography (PE:EtOAc=15:1) gave 200 mg (18%) of the title compound as a yellow solid.

¹H NMR (300 MHz, CDCl₃): δ 2.11-2.15 (2H, m), 2.64 (2H, t, J=6.3 Hz), 2.85 (2H, t, J=6.3 Hz), 3.28 (2H, t, J=8.7 Hz), 4.65 (2H, t, J=8.7 Hz), 7.15 (1H, d, J=7.8 Hz), 7.62 (1H, d, J=7.8 Hz). [M+H] Calc'd for C₁₂H₁₂O₂, 189; Found, 189.

Preparation 92d: 2H,3H,8H,9H-naphtho[1,2-b]furan-6-ylmethanamine, Hydrochloride

The title compound was prepared in 72% yield from Preparation 92c according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₃H₁₅NO, 202; Found, 202.

Preparation 92e: 2H,3H,6H,7H,8H,9H-naphtho[1,2-b]furan-6-ylmethanamine

The title compound was prepared in quantitative yield from Preparation 92d according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₃H₁₇NO, 204; Found, 204.

Preparation 92f: methyl 3-({2H,3H,6H,7H,8H,9H-naphtho[1,2-b]furan-6-ylmethyl}amino)pyridine-4-carboxylate

The title compound was prepared in 26% yield from Preparation 92f according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₀H₂₂N₂O₃, 339; Found, 339.

Example 92: 3-({2H,3H,6H,7H,8H,9H-naphtho[1,2-b]furan-6-ylmethyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 81% yield from Preparation 92f according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.65-1.84 (4H, m), 2.44-2.50 (1H, m), 2.50-2.61 (1H, m), 3.05-3.14 (3H, m), 3.41-3.56 (2H, m), 4.99 (2H, t, J=8.4 Hz), 6.78 (1H, d, J=7.6 Hz), 6.99 (1H, d, J=7.6 Hz), 7.57 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=5.2 Hz), 8.35 (1H, s). [M+H] Calc'd for C₁₉H₂₀N₂O₃, 325; Found, 325.

Preparation 93a: (6,7-dimethyl-2H-chromen-4-yl)methanamine, Hydrochloride

The title compound was prepared in 26% yield from 6,7-dimethyl-3,4-dihydro-2H-1-benzopyran-4-one according to the general procedure for Preparation 3a. ¹H NMR (400 MHz, DMSO-d₆): δ 1.55 (2H, br s), 1.81-1.99 (2H, m), 2.09 (6H, s), 2.54-2.60 (2H, m), 2.81-2.88 (1H, m), 3.96-4.07 (2H, m), 6.50 (1H, s), 6.90 (1H, s). [M+H] calc'd for C₁₂H₁₅NO, 190; found 190.

Preparation 93b: (6,7-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)methanamine

The title compound was prepared in quantitative yield from Preparation 93a according to the general procedure for Preparation 3e. ¹H NMR (400 MHz, DMSO-d₆): δ 1.55 (2H, br s), 1.81-1.99 (2H, m), 2.09 (6H, s), 2.54-2.60 (2H, m), 2.81-2.88 (1H, m), 3.96-4.07 (2H, m), 6.50 (1H, s), 6.90 (1H, s). [M+H] calc'd for C₁₂H₁₇NO, 192; found 192.

Example 93: 3-{[(6,7-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]amino}pyridine-4-carboxylic Acid

The title compound was prepared in 21% yield from Preparation 93b according to the general procedure for Example 13. ¹H NMR (400 MHz, DMSO-d₆): δ 1.81-1.99 (2H, m), 2.11 (3H, s), 2.12 (3H, s), 3.02-3.06 (1H, m), 3.43-3.67 (2H, m), 4.06-4.17 (2H, m), 6.56 (1H, s), 7.04 (1H, s), 7.57 (1H, d, J=5.0 Hz), 7.69 (1H, br s), 7.85 (1H, d, J=5.0 Hz), 8.42 (s, 1H), 13.38 (1H, br s). [M+H] calc'd for C₁₈H₂₀N₂O₃, 313; found 313.

Preparation 94a: (6-methoxy-7-methyl-3,4-dihydronaphthalen-1-yl)methanamine, Hydrochloride

The title compound was prepared in 56% yield from 6-methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-1-one according to the general procedure for Preparation 3a. [M+H] calc'd for C₁₃H₁₇NO, 204; found 204.

Preparation 94b: (6-methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in quantitative yield from Preparation 94a according to the general procedure for Preparation 3e. ¹H NMR (400 MHz, CDCl₃): δ 1.65-1.85 (6H, m), 2.17 (3H, s), 2.69-2.75 (3H, m), 2.84-2.97 (2H, m), 3.79 (3H, s), 6.53 (1H, s), 6.95 (1H, s). [M+H] calc'd for C₁₃H₁₉NO, 206; found 206.

Preparation 94c: methyl 3-{[(6-methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 66% yield from Preparation 94b according to the general procedure for Preparation 4d. ¹H NMR (400 MHz, DMSO-d₆): δ 1.76-1.92 (4H, m), 2.18 (3H, s), 2.74-2.79 (2H, m), 3.06-3.10 (1H, m), 3.34-3.41 (1H, m), 3.52-3.59 (1H, m), 3.80 (3H, s), 3.90 (3H, s), 6.56 (1H, s), 7.00 (1H, s), 7.58 (1H, br s), 7.63 (1H, d, J=5.1 Hz), 7.90 (1H, d, J=5.1 Hz), 8.34 (1H, s). [M+H] calc'd for C₂₀H₂₄N₂O₃, 341; found 341.

Example 94: 3-{[(6-methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic Acid

The title compound was prepared in 63% yield from Preparation 94c according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.62-1.81 (4H, m), 2.08 (3H, s), 2.66-2.71 (2H, m), 2.97-3.01 (1H, m), 3.35-3.42 (1H, m), 3.50-3.56 (1H, m), 3.73 (3H, s), 6.61 (1H, s), 7.05 (1H, s), 7.57 (1H, d, J=5.0 Hz), 7.71 (1H, br s), 7.83 (1H, d, J=5.0 Hz), 8.35 (1H, s). [M+H] calc'd for C₁₉H₂₂N₂O₃, 327; found 327.

Preparation 95a: 4-(3,5-dimethoxyphenyl)but-3-enoic Acid

To a solution of (2-carboxyethyl)triphenylphosphonium bromide (13.7 g, 33 mmol) in dry THF (50 mL) was added NaHMDS (33 mL, 66 mmol) dropwise at −20° C. under N₂ and the reaction stirred for 20 min. The reaction was cooled to −78° C. and 3,5-dimethoxybenzaldehyde (5.0 g, 30 mmol) was added, and the reaction mixture stirred overnight while warming to rt. The reaction was quenched with water and extracted with EtOAc. The aqueous layer was acidified to pH=2 with dilute HCl solution and extracted with EtOAc again. The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated to give 2.54 g (38%) of the title compound as an orange gum. [M+H] Calc'd for C₁₂H₁₄O₄, 223; Found, 223.

Preparation 95b: 4-(3,5-dimethoxyphenyl)butanoic Acid

To a solution of Preparation 95a (2.54 g, 11.4 mmol) in MeOH (25 mL) and conc. HCl (three drops) under N₂ was added 10% Pd/C (0.5 g) at rt. The suspension was stirred for 3 h under 50 psi of H₂. The reaction mixture was filtered through Celite and concentrated to give 2.27 g (88%) of the title compound as colorless oil. [M+H] Calc'd for C₁₂H₁₆O₄, 225; Found, 225.

Preparation 95c: 6,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-one

The mixture of Preparation 95b (2.27 g, 10 mmol) and PPA (30 g) was heated at 95° C. for 30 min. The gum was dissolved in water and extracted with EtOAc. Organics were washed with brine, dried (Na₂SO₄), and concentrated. The residue was purified by silica gel chromatography to give 1.2 g (57%) of the title compound as tan oil. ¹H NMR (400 MHz, CD₃OD): δ 1.96 (2H, t, J=6.2 Hz), 2.51 (2H, t, J=6.4 Hz), 2.85 (2H, t, J=6.0 Hz), 3.81 (3H, s), 3.83 (3H, s), 6.38 (2H, d, J=2.4 Hz). [M+H] Calc'd for C₁₂H₁₄O₃, 207; Found, 207.

Preparation 95d: (6,8-dimethoxy-3,4-dihydronaphthalen-1-yl)methanamine, Hydrochloride

The title compound was prepared in 46% yield from Preparation 95c according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₃H₁₇NO₂, 220; Found, 220.

Preparation 95e: (6,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in 87% yield from Preparation 95d according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₃H₁₉NO₂, 222; Found, 222.

Preparation 95f: methyl 3-{[(6,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 38% yield from Preparation 95e according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₀H₂₄N₂O₄, 357; Found, 357.

Example 95: 3-{[(6,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic Acid

The title compound was prepared in 46% yield from Preparation 95f according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.51-1.57 (1H, m), 1.63-1.67 (1H, m), 1.81-1.93 (2H, m), 2.61-2.75 (2H, m), 3.14-3.24 (2H, m), 3.47 (1H, d, J=10.8 Hz), 3.70 (3H, s), 3.84 (3H, s), 6.28 (1H, d, J=2.0 Hz), 6.39 (1H, d, J=2.0 Hz), 7.55 (1H, d, J=5.2 Hz), 7.81 (1H, d, J=5.2 Hz), 8.53 (1H, s). [M+H] Calc'd for C₁₉H₂₂N₂O₄, 343; Found, 343.

Preparation 96a: 4-(4-fluoro-3-methoxyphenyl)but-3-enoic Acid

To a solution of (2-carboxyethyl)triphenylphosphonium bromide (14.8 g, 35.7 mmol) in THF (40 mL) was added NaHMDS (35.8 mL, 71.5 mmol) at −20° C., and the reaction was stirred for 20 min. 4-Fluoro-3-methoxybenzaldehyde (5.0 g, 32.5 mmol) was added to the reaction at −78° C., and the reaction was stirred overnight while warming to rt. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). Organics were washed with brine (30 mL), dried (Na₂SO₄), and concentrated to give 6.0 g (88%) of the crude title compound as a yellow solid. [M+H] Calc'd for C₁₁H₁₁FO₃, 211; Found, 211.

Preparation 96b: 4-(4-fluoro-3-methoxyphenyl)butanoic Acid

To a solution of Preparation 96a (6.0 g, 28.6 mmol) in MeOH (30 mL) under N₂ was added 10% Pd/C (1.2 g), and the mixture was stirred at rt overnight under 50 psi of H₂. The reaction mixture was filtered through Celite and concentrated to give 5.8 g (96%) of the crude title compound as an off-white solid. [M+H] Calc'd for C₁₁H₁₃FO₃, 213; Found, 213.

Preparation 96c: 7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-one

PPA (30 g) was added to Preparation 96b (5.8 g, 27.4 mmol) at rt, and the reaction was stirred at 95° C. for 0.5 h. The solution was poured into water (50 mL) at rt, and extracted with EtOAc (3×50 mL). Organics were washed with brine (50 mL), dried (Na₂SO₄), and concentrated. Purification by silica gel chromatography (PE:EtOAc=3:1) gave 3.1 g (58%) of the title compound as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 2.09-2.16 (2H, m), 2.60 (2H, t, J=6.4 Hz), 2.91 (2H, t, J=6.0 Hz), 3.94 (3H, s), 6.75 (1H, d, J=8.0 Hz), 7.32 (1H, d, J=11.6 Hz). [M+H] Calc'd for C₁₁H₁₁FO₂, 195; Found, 195.

Preparation 96d: (7-fluoro-6-methoxy-3,4-dihydronaphthalen-1-yl)methanamine, Hydrochloride

The title compound was prepared in 83% yield from Preparation 96c according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₂H₁₄FNO, 208; Found, 208.

Preparation 96e: (7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in quantitative yield from Preparation 96d according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₂H₁₆FNO, 210; Found, 210.

Preparation 96f: methyl 3-({[(1S)-7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate, and Preparation 97f: methyl 3-({[(1R)-7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 25% yield from Preparation 96e according to the general procedure for Preparation 1e. [M+H] Calc'd for C₁₉H₂₁FN₂O₃, 345; Found, 345.

Separation by chiral HPLC (Column: Chiralcel: IA Sum 4.6*250 mm, Mobile phase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 40% yield of Preparation 96f (7.937 min) and 37% of Preparation 97f (10.383 min), each as a colorless oil.

Example 96: 3-({[(1S)-7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 65% yield from Preparation 96f according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.63-1.84 (4H, m), 2.64-2.74 (2H, m), 3.01-3.06 (1H, m), 3.38-3.44 (1H, m), 3.56-3.60 (1H, m), 3.79 (3H, s), 6.85 (1H, d, J=8.8 Hz), 7.17 (1H, d, J=13.2 Hz), 7.56 (1H, d, J=5.2 Hz), 7.83 (1H, d, J=5.2 Hz), 8.38 (1H, s).

[M+H] Calc'd for C₁₈H₁₉FN₂O₃, 331; Found, 331.

Example 97: 3-({[(1R)-7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 64% yield from Preparation 97f according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.63-1.86 (4H, m), 2.63-2.74 (2H, m), 3.01-3.04 (1H, m), 3.39-3.43 (1H, m), 3.56-3.60 (1H, m), 3.79 (3H, s), 6.86 (1H, d, J=9.2 Hz), 7.17 (1H, d, J=12.8 Hz), 7.55 (1H, d, J=5.2 Hz), 7.83 (1H, d, J=5.2 Hz), 8.38 (1H, s).

[M+H] Calc'd for C₁₈H₁₉FN₂O₃, 331; Found, 331.

Preparation 98a: 5-bromo-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-one

To a suspension of 6-methoxy-1-tetralone (2.0 g, 11.4 mmol) and NBS (2.0 g, 11.4 mmol) in H₂O (30 mL) was added conc. H₂SO₄ (1.2 mL, 22.7 mmol) at rt. The reaction was stirred at 60° C. for 3 h. The mixture was filtered, and concentrated. Purification by prep-HPLC gave 1.2 g (41%) of the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 2.13-2.18 (2H, m), 2.61 (2H, t, J=6.0 Hz), 3.03 (2H, t, J=6.0 Hz), 3.97 (3H, s), 6.88 (1H, d, J=8.8 Hz), 8.06 (1H, d, J=8.8 Hz). [M+H] Calc'd for C₁₁H_(n)BrO₂, 255, 257; Found, 255, 257.

Preparation 98b: 6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1-one

To a suspension of Preparation 98a (100 mg, 0.39 mmol), potassium methyltrifluoroborate (48 mg, 0.39 mmol) and Cs₂CO₃ (381 mg, 1.2 mmol) in H₂O (2 mL) and DMF (18 mL) was added Pd(dppf)Cl₂DCM (32 mg, 0.04 mmol) at rt under N₂. The reaction was stirred at 120° C. overnight. The reaction was filtered and concentrated. Purification by silica gel chromatography (PE:EtOAc=15:1) gave 40 mg (54%) of the title compound as a white solid. [M+H] Calc'd for C₁₂H₁₄O₂, 191; Found, 191.

Preparation 98c: (6-methoxy-5-methyl-3,4-dihydronaphthalen-1-yl)methanamine, Hydrochloride

The title compound was prepared in 42% yield from Preparation 98b according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₃H₁₇NO, 204; Found, 204.

Preparation 98d: (6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in quantitative yield from Preparation 98c according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₃H₁₉NO, 206; Found, 206.

Preparation 98d: methyl 3-({[(1S)-6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate, and Preparation 99d: methyl 3-({[(1R)-6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 43% yield from Preparation 99c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₁₉H₂₁FN₂O₃, 345; Found, 345.

Separation by chiral HPLC (Column: Chiralcel: OJ-H Sum 4.6*250 mm, Mobile phase: CO₂:MeOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 40% yield of Preparation 99d (2.17 min) and 28% of Preparation 98d (3.10 min), each as a yellow oil.

Example 98: 3-({[(1S)-6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 63% yield from Preparation 98d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.70-1.77 (3H, m), 1.83-1.86 (1H, m), 2.03 (3H, s), 2.52-2.56 (1H, m), 2.63-2.67 (1H, m), 3.03-3.06 (1H, m), 3.40-3.45 (1H, m), 3.50-3.55 (1H, m), 3.74 (3H, s), 6.78 (1H, d, J=8.4 Hz), 7.12 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=4.8 Hz), 8.36 (1H, s). [M+H] Calc'd for C₁₉H₂₂N₂O₃, 327; Found, 327.

Example 99: 3-({[(1R)-6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 93% yield from Preparation 99d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.70-1.77 (3H, m), 1.83-1.86 (1H, m), 2.03 (3H, s), 2.52-2.56 (1H, m), 2.63-2.67 (1H, m), 3.03-3.06 (1H, m), 3.40-3.45 (1H, m), 3.50-3.55 (1H, m), 3.74 (3H, s), 6.78 (1H, d, J=8.4 Hz), 7.12 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=4.8 Hz), 8.36 (1H, s). [M+H] Calc'd for C₁₉H₂₂N₂O₃, 327; Found, 327.

Preparation 100a: 7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-one

To a solution of 7-bromo-4-chromanone (2.0 g, 8.8 mmol) in dioxane (30 mL) was added 2-methylphenylboronic acid (1.8 g, 13.2 mmol), Pd(PPh₃)₄ (0.5 g, 0.44 mmol) and Na₂CO₃ (2.8 g, 26.4 mmol). The mixture was stirred at 100° C. under nitrogen overnight. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=10:1) to give 2.1 g (quantitative) of the title compound as an off-white solid. ¹H NMR (300 MHz, CDCl₃): δ2.29 (s, 3H), 2.85 (t, J=6.3 Hz, 2H), 4.59 (t, J=6.3 Hz, 2H), 6.94 (s, 1H), 7.00 (d, J=8.1 Hz, 1H), 7.19-7.32 (m, 4H), 7.93 (d, J=8.1 Hz, 1H). [M+H] Calc'd for C₁₆H₁₄O₂, 239; Found, 239.

Preparation 100b: [7-(2-methylphenyl)-2H-chromen-4-yl]methanamine, Hydrochloride

The title compound was prepared in 47% yield from Preparation 100a according to the general procedure for Preparation 3a. [M+H] Calc'd for C₁₇H₁₇NO, 252; Found, 252.

Preparation 100c: [7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in quantitative yield from Preparation 100b according to the general procedure for Preparation 3e. [M+H] Calc'd for C₁₇H₁₉NO, 254; Found, 254.

Preparation 100d: methyl 3-({[(4S)-7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 101d: methyl 3-({[(4R)-7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The racemate (440 mg) of the title compounds was prepared in 25% yield from Preparation 100c according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₄H₂₄N₂O₃, 389; Found, 389.

Separation by chiral HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 179 mg (41%) of Preparation 100d (7.49 min) and 189 mg (43%) of Preparation 101d (8.82 min), each as a colorless oil.

Example 100: 3-({[(4S)-7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 80% yield from Preparation 100d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.88-1.96 (m, 1H), 2.02-2.09 (m, 1H), 2.23 (s, 3H), 3.16-3.21 (m, 1H), 3.54-3.59 (m, 1H), 3.74-3.79 (m, 1H), 4.17-4.28 (m, 2H), 6.72 (d, J=1.6 Hz, 1H), 6.82 (dd, J=7.6 Hz, 1.6 Hz, 1H), 7.16-7.17 (m, 1H), 7.20-7.28 (m, 3H), 7.37 (d, J=7.6 Hz, 1H), 7.58 (d, J=4.8 Hz, 1H), 7.86 (d, J=4.8 Hz, 1H), 8.45 (s, 1H). [M+H] Calc'd for C₂₃H₂₂N₂O₃, 375; Found, 375.

Example 101: 3-({[(4R)-7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 74% yield from Preparation 101d according to the general procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.88-1.96 (m, 1H), 2.00-2.09 (m, 1H), 2.23 (s, 3H), 3.17-3.22 (m, 1H), 3.54-3.62 (m, 1H), 3.74-3.79 (m, 1H), 4.17-4.29 (m, 2H), 6.72 (d, J=1.6 Hz, 1H), 6.82 (dd, J=7.6 Hz, 1.6 Hz, 1H), 7.15-7.17 (m, 1H), 7.20-7.29 (m, 3H), 7.37 (d, J=7.6 Hz, 1H), 7.58 (d, J=4.8 Hz, 1H), 7.86 (d, J=4.8 Hz, 1H), 8.45 (s, 1H).

[M+H] Calc'd for C₂₃H₂₂N₂O₃, 375; Found, 375.

Preparation 102a: tert-butyl N-{[(4R)-7-(5-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 80% yield from 5-fluoro-2-methoxyphenylboronic acid and Preparation 18d according to the procedures for Preparation 43a. [M+H] Calc'd for C₂₂H₂₆FNO₄, 388; Found, 388.

Preparation 102b: [(4R)-7-(5-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 78% yield from Preparation 102a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₇H₁₈FNO₂, 288; Found, 288.

Preparation 102c: methyl 3-({[(4R)-7-(5-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 56% yield from Preparation 102b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₃FN₂O₄, 423; Found, 423.

Example 102: 3-({[(4R)-7-(5-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 90% yield from Preparation 102c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.90-1.94 (1H, m), 2.00-2.04 (1H, m), 3.15-3.19 (1H, m), 3.51-3.56 (1H, m), 3.72-3.76 (4H, m), 4.19-4.25 (2H, m), 6.91 (1H, s), 6.97 (1H, d, J=8.4 Hz), 7.07-7.17 (3H, m), 7.35 (1H, d, J=7.6 Hz), 7.59 (1H, d, J=5.2 Hz), 7.86 (1H, d, J=4.4 Hz), 8.44 (1H, s). [M+H] Calc'd for C₂₃H₂₁FN₂O₄, 409; Found, 409.

Preparation 103a: tert-butyl N-{[(1R)-6-[(4-cyanophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 47% yield from Preparation 6d and 4-cyano-N-methylaniline according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₄H₂₉N₃O₂, 392; found 392.

Preparation 103b: 4-{[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl](methyl)amino}benzonitrile

The title compound was prepared in 95% yield from Preparation 103a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₉H₂₁N₃, 292; Found, 292.

Preparation 103c: methyl 3-({[(1R)-6-[(4-cyanophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 68% yield from Preparation 103b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₆H₂₆N₄O₂, 427; Found, 427.

Example 103: 3-({[(1R)-6-[(4-cyanophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 48% yield from Preparation 103c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.62-1.87 (4H, m), 2.69-2.75 (2H, m), 3.05-3.11 (1H, m), 3.28 (3H, s), 3.45-3.51 (1H, m), 3.60-3.68 (1H, m), 6.74 (2H, d, J=8.9 Hz), 6.98-7.03 (2H, m), 7.40 (1H, d, J=8.9 Hz), 7.53 (2H, d, J=8.9 Hz), 7.55 (1H, d, J=5.0 Hz), 7.72 (1H, br s), 7.84 (1H, d, J=5.0 Hz), 8.37 (1H, s), 13.37 (1H, br s). [M+H] Calc'd for C₂₅H₂₄N₄O₂, 436; Found, 413.

Preparation 104a: tert-butyl N-{[(4R)-7-[(2,4-difluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 29% yield from Preparation 18d and 2,4-difluoro-N-methylaniline according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₂H₂₆F₂N₂O₃, 405; found 405.

Preparation 104b: (4R)-4-(aminomethyl)-N-(2,4-difluorophenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 78% yield from Preparation 104a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₇H₁₈F₂N₂O, 305; Found, 305.

Preparation 104c: methyl 3-({[(4R)-7-[(2,4-difluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 70% yield from Preparation 104b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₁₃F₂N₃O₃, 440; Found, 440.

Example 104: 3-({[(4R)-7-[(2,4-difluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 34% yield from Preparation 104c according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.84-1.86 (1H, m), 1.93-1.95 (1H, m), 2.99-3.03 (1H, m), 3.14 (3H, s), 3.42-3.46 (1H, m), 3.58-3.62 (1H, m), 4.08-4.15 (2H, m), 6.00 (1H, d, J=2.4 Hz), 6.14 (1H, d, J=6.3 Hz), 7.07-7.16 (2H, m), 7.31-7.40 (2H, m), 7.55 (1H, d, J=5.1 Hz), 7.82 (1H, d, J=4.8 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₃H₂₁F₂N₃O₃, 426; Found, 426.

Preparation 105a: tert-butyl N-{[(4R)-7-[methyl(3-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 33% yield from Preparation 18d and 3-methyl-N-methylaniline according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₃H₃₀N₂O₃, 383; found 383.

Preparation 105b: (4R)-4-(aminomethyl)-N-methyl-N-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 93% yield from Preparation 105a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₈H₂₂N₂O, 283; Found, 283.

Preparation 105c: 3-({[(4R)-7-[methyl(3-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 77% yield from Preparation 105b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Example 105: 3-({[(4R)-7-[methyl(3-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 39% yield from Preparation 105c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.86-1.87 (1H, m), 1.96-1.98 (1H, m), 2.25 (3H, s), 3.04-3.07 (1H, m), 3.18 (3H, s), 3.43-3.50 (1H, m), 3.64-3.69 (1H, m), 4.11-4.18 (2H, m), 6.33 (1H, d, J=2.0 Hz), 6.46 (1H, d, J=6.0 Hz), 6.76-6.83 (3H, m), 7.13-7.18 (2H, m), 7.57 (1H, d, J=5.2 Hz), 7.84 (1H, d, J=5.2 Hz), 8.40 (1H, s). [M+H] Calc'd for C₂₄H₂₅N₃O₃, 404; Found, 404.

Preparation 106a: tert-butyl N-{[(1R)-6-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a suspension of Preparation 6d (200 mg, 0.59 mmol), pyrrolidine (84 mg, 1.18 mmol), JohnPhos (27 mg, 0.09 mmol) and t-BuONa (57 mg, 0.59 mmol) in toluene (10 mL) was added Pd₂dba₃ (55 mg, 0.06 mmol) under N₂, and the reaction was refluxed for 3 h. The reaction was filtered and concentrated. Purification by HPLC gave 144 mg (73%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₀H₃₀N₂O₂, 331; Found, 331.

Preparation 106b: [(1R)-6-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 95% yield from Preparation 106a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₅H₂₂N₂, 231; Found, 231.

Preparation 106c: methyl 3-({[(1R)-6-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 19% yield from Preparation 106b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₂H₂₇N₃O₂, 366; Found, 366.

Example 106: 3-({[(1R)-6-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 15% yield from Preparation 106c according to the general procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.61-1.62 (1H, m), 1.74-1.78 (3H, m), 1.89-1.94 (4H, m), 2.63-2.66 (2H, m), 2.95-2.97 (1H, m), 3.14-3.20 (2H, m), 3.25-3.35 (2H, m), 3.38-3.49 (2H, m), 6.23 (1H, s), 6.34 (1H, d, J=6.0 Hz), 7.07 (1H, d, J=8.7 Hz), 7.55-7.56 (1H, d, J=4.5 Hz), 7.77-7.78 (1H, d, J=4.8 Hz), 8.23 (1H, s). [M+H] Calc'd for C₂₁H₂₅N₃O₂, 352; Found, 352.

Preparation 107a: tert-butyl N-{[(4R)-7-(2-chloro-5-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 68% yield from 2-chloro-5-methoxyphenylboronic acid and Preparation 18d according to the procedures for Preparation 43a. [M+H] Calc'd for C₂₂H₂₆ClNO₄, 404; Found, 404.

Preparation 107b: [(4R)-7-(2-chloro-5-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 79% yield from Preparation 107a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₇H₁₈ClNO₂, 304; Found, 304.

Preparation 107c: methyl 3-({[(4R)-7-(2-chloro-5-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 48% yield from Preparation 107b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₃ClN₂O₄, 439; Found, 439.

Example 107: 3-({[(4R)-7-(2-chloro-5-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 84% yield from Preparation 107c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.90-1.95 (1H, m), 2.02-2.06 (1H, m), 3.18-3.21 (1H, m), 3.53-3.59 (1H, m), 3.74-3.79 (4H, m), 4.19-4.28 (2H, m), 6.84 (1H, s), 6.90-6.97 (3H, m), 7.40-7.44 (2H, m), 7.60 (1H, d, J=5.2 Hz), 7.87 (1H, d, J=5.2 Hz), 8.47 (1H, s). [M+H] Calc'd for C₂₃H₂₁ClN₂O₄, 425; Found, 425.

Preparation 108a: tert-butyl N-{[(1R)-6-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 58% yield from Preparation 6d and 3,4-dihydro-2H-1,4-benzoxazine according to the general procedure for Preparation 9a. [M+H] Calc'd for C₂₄H₃₀N₂O₃, 395; Found, 395.

Preparation 108b: [(1R)-6-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 93% yield from Preparation 108a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₉H₂₂N₂O, 295; Found, 295.

Preparation 108c: methyl 3-({[(1R)-6-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 55% yield from Preparation 108b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₆H₂₇N₃O₃, 430; Found, 430.

Example 108: 3-({[(1R)-6-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 86% yield from Preparation 108c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.65-1.70 (1H, m), 1.79-1.85 (3H, m), 2.69-2.73 (2H, m), 3.08-3.11 (1H, m), 3.43-3.49 (1H, m), 3.58-3.65 (3H, m), 4.22 (2H, t, J=4.0 Hz), 6.67-6.71 (2H, m), 6.76-6.81 (2H, m), 6.97-7.01 (2H, m), 7.31 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=4.8 Hz), 7.84 (1H, d, J=4.8 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₅H₂₅N₃O₃, 416; Found, 416.

Preparation 109a: 3,5-difluoro-N-methylaniline

A solution of 3,5-difluoroaniline (5.0 g, 38.7 mmol) in HCOOH (15 mL) was heated to reflux for 4 h. The mixture was poured into ice-water and stirred for 0.5 h. The white solid was collected by filtration, and dried under vacuum to give 4.8 g (79%) of crude N-(3,5-difluorophenyl)formamide.

To the solution of LiAlH₄ (3.0 g, 78.9 mmol) in dry THF (50 mL) was added a solution of N-(3,5-difluorophenyl)formamide (4.8 g, 30.6 mmol) in dry THF (50 mL) at r.t. The mixture was stirred overnight and then quenched with addition of water (3.0 mL), aqueous 10% NaOH (3.0 mL), and water (9.0 ml). The reaction mixture was filtered and extracted with EtOAc. Organics were dried (Na₂SO₄), and concentrated to give 3.8 g (86%) of the title compound as a pale brown oil.

Preparation 109b: tert-butyl N-{[(4R)-7-[(3,5-difluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 74% yield from Preparation 18d and Preparation 109a according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₂H₂₆₇F₂N₂O₃, 405; found 405.

Preparation 109c: (4R)-4-(aminomethyl)-N-(3,5-difluorophenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 94% yield from Preparation 109b according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₇H₁₈F₂N₂O, 305; Found, 305.

Preparation 109d: 3-({[(4R)-7-[(3,5-difluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 38% yield from Preparation 109c according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₃F₂N₃O₃, 440; Found, 440.

Example 109: 3-({[(4R)-7-[(3,5-difluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 86% yield from Preparation 109c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.88-1.92 (1H, m), 1.98-2.05 (1H, m), 3.12-3.18 (1H, m), 3.21 (3H, s), 3.51-3.56 (1H, m), 3.71-3.75 (1H, m), 4.15-4.27 (2H, m), 6.34-6.37 (2H, m), 6.45-6.50 (1H, m), 6.63 (1H, d, J=2.4 Hz), 6.71 (1H, dd, J=2.0, 8.0 Hz), 7.35 (1H, d, J=8.4 Hz), 7.57 (1H, d, J=5.2 Hz), 7.84 (1H, d, J=5.2 Hz), 8.42 (1H, s). [M+H] Calc'd for C₂₃H₂₁F₂N₃O₃, 426; Found, 426.

Preparation 110a: tert-butyl N-{[(4R)-7-[(3-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 37% yield from Preparation 18d and 3-chloro-N-methylaniline according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₂H₂₇ClN₂O₃, 403; found 403.

Preparation 110b: (4R)-4-(aminomethyl)-N-(3-chlorophenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 79% yield from Preparation 110a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₇H₁₉ClN₂O, 303; Found, 303.

Preparation 110c: 3-({[(4R)-7-[(3-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 50% yield from Preparation 110b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₄ClN₃O₃, 438; Found, 438.

Example 110: 3-({[(4R)-7-[(3-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 82% yield from Preparation 110c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.86-1.90 (1H, m), 1.98-2.02 (1H, m), 3.10-3.14 (1H, m), 3.21 (3H, s), 3.48-3.54 (1H, m), 3.68-3.73 (1H, m), 4.16-4.24 (2H, m), 6.52 (1H, s), 6.62-6.64 (1H, m), 6.79-6.85 (3H, m), 7.21 (1H, t, J=8.0 Hz), 7.29 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=5.2 Hz), 7.85 (1H, d, J=5.2 Hz), 8.42 (1H, s). [M+H] Calc'd for C₂₃H₂₂ClN₃O₃, 424; Found, 424.

Preparation 111a: tert-butyl N-{[(4R)-7-[methyl(2-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 27% yield from Preparation 18d and N,2-dimethylaniline according to the general procedure for Preparation 9a. [M+H] calc'd for C₂₃H₃₀N₂O₃, 383; found 383.

Preparation 111b: (4R)-4-(aminomethyl)-N-methyl-N-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 96% yield from Preparation 111a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₈H₂₂N₂O, 283; Found, 283.

Preparation 111c: methyl 3-({[(4R)-7-[methyl(2-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 11% yield from Preparation 111b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Example 111: 3-({[(4R)-7-[methyl(2-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 58% yield from Preparation 111c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.83-1.93 (1H, m), 1.94-1.96 (1H, m), 2.07 (3H, m), 2.97-3.01 (1H, m), 3.11 (3H, s), 3.37-3.45 (1H, m), 3.58-3.62 (1H, m), 4.05-4.15 (2H, m), 5.84 (1H, s), 5.98-6.00 (1H, m), 7.04 (1H, d, J=8.8 Hz), 7.09-7.11 (1H, m), 7.18-7.32 (3H, m), 7.56 (1H, t, J=5.2 Hz), 7.83 (1H, d, J=4.8 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₄H₂₅N₃O₃, 404; Found, 404.

Preparation 112a: 4-fluoro-3-methoxy-N-methylaniline

The title compound was prepared in 75% yield from 4-fluoro-3-methoxy-aniline according to the general procedure for Preparation 109a.

Preparation 112b: tert-butyl N-{[(4R)-7-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 49% yield from Preparation 18d and Preparation 112a according to the general procedure for Preparation 9a. [M+H] calc'd for C₂₃H₂₉FN₂O₄, 417; found 417.

Preparation 112c: (4R)-4-(aminomethyl)-N-(4-fluoro-3-methoxyphenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 94% yield from Preparation 112b according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₈H₂₁FN₂O₂, 317; Found, 317.

Preparation 112d: methyl 3-({[(4R)-7-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 66% yield from Preparation 112c according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₅H₂₆FN₃O₄, 450; Found, 450.

Example 112: 3-({[(4R)-7-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 78% yield from Preparation 112d according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.82-1.87 (1H, m), 1.91-2.00 (1H, m), 3.03-3.07 (1H, m), 3.18 (3H, s), 3.43-3.50 (1H, m), 3.61-3.68 (1H, m), 3.78 (3H, s), 4.08-4.18 (2H, m), 6.27 (1H, d, J=2.4 Hz), 6.41 (1H, dd, J=8.4, 2.4 Hz), 6.54-6.58 (1H, m), 6.82-6.85 (1H, m), 7.09-7.16 (2H, m), 7.56 (1H, d J=5.2 Hz), 7.84 (1H, d, J=5.2 Hz), 8.39 (1H, s). [M+H] Calc'd for C₂₄H₂₄FN₃O₄, 438; Found, 438.

Preparation 113a: tert-butyl N-{[(1R)-6-[methyl(oxan-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a solution of Preparation 6d (400 mg, 1.18 mmol) in toluene (10 mL) was added N-methyloxan-4-amine (270 mg, 2.36 mmol), Cs₂CO₃ (770 mg, 2.36 mmol), BINAP (38 mg, 0.06 mmol) and Pd(OAc)₂ (14 mg, 0.06 mmol). The mixture was stirred overnight at 100° C. under N₂. The mixture was filtered and concentrated, and the residue was purified by HPLC to give 70 mg (15%) of the title compound as a yellow gum. [M+H] Calc'd for C₂₂H₃₄N₂O₃, 375; Found, 375.

Preparation 113b: N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-methyloxan-4-amine

The title compound was prepared in 99% yield from Preparation 113a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₇H₂₆N₂O, 275; Found, 275.

Preparation 113c: methyl 3-({[(1R)-6-[methyl(oxan-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 26% yield from Preparation 113b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₃₁N₃O₃, 410; Found, 410.

Example 113: 3-({[(1R)-6-[methyl(oxan-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 10% yield from Preparation 113c according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.61-1.68 (3H, m), 1.83-2.06 (6H, m), 2.87-2.94 (2H, m), 3.25 (3H, s), 3.34-3.44 (2H, m), 3.62-3.65 (2H, m), 3.81-3.90 (1H, m), 4.01-4.06 (2H, m), 7.28-7.30 (2H, m), 7.51 (1H, d, J=7.8 Hz), 7.89-7.91 (1H, m), 8.08 (1H, d, J=5.4 Hz), 8.26 (1H, d, J=1.8 Hz). [M+H] Calc'd for C₂₃H₂₉N₃O₃, 396; Found, 396.

Preparation 114a: tert-butyl N-{[(1R)-6-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 41% yield from Preparation 6d and Preparation 112a according to the general procedure for Preparation 6e. [M+H] calc'd for C₂₄H₃₁FN₂O₃, 415; found 415.

Preparation 114b: (5R)-5-(aminomethyl)-N-(4-fluoro-3-methoxyphenyl)-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in 85% yield from Preparation 114a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₉H₂₃FN₂O, 315; Found, 315.

Preparation 114c: methyl 3-({[(1R)-6-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 62% yield from Preparation 114b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₆H₂₈FN₃O₃, 450; Found, 450.

Example 114: 3-({[(1R)-6-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 98% yield from Preparation 114c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.64-1.84 (4H, m), 2.64-2.68 (2H, m), 3.03-3.06 (1H, m), 3.21 (3H, s), 3.38-3.45 (1H, m), 3.54-3.58 (1H, m), 3.76 (3H, s), 6.46-6.50 (1H, m), 6.70-6.78 (3H, m), 7.06-7.11 (1H, m), 7.20 (1H, d, J=8.4 Hz), 7.56 (1H, t, J=5.2 Hz), 7.82 (1H, d, J=5.2 Hz), 8.34 (1H, s). [M+H] Calc'd for C₂₅H₂₆FN₃O₃, 436; Found, 436.

Preparation 115a: tert-butyl N-{[(1R)-6-[(3-cyanophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 36% yield from Preparation 6e and 3-cyano-N-methylaniline according to the general procedure for Preparation 9a. [M+H] calc'd for C₂₄H₂₉N₃O₂, 392; found 392.

Preparation 115b: 3-{[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl](methyl)amino}benzonitrile

The title compound was prepared in 97% yield from Preparation 115a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₉H₂₁N₃, 292; Found, 292.

Preparation 115c: methyl 3-({[(1R)-6-[(3-cyanophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 69% yield from Preparation 115b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₆H₂₆N₄O₂, 427; Found, 427.

Example 115: 3-({[(1R)-6-[(3-cyanophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 76% yield from Preparation 115c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.66-1.87 (4H, m), 2.72-2.74 (2H, m), 3.11-3.17 (1H, m), 3.25 (3H, s), 3.51-3.53 (1H, m), 3.62-3.65 (1H, m), 6.95-6.96 (2H, m), 7.02-7.04 (1H, m), 7.12-7.16 (2H, m), 7.32-7.37 (2H, m), 7.77 (1H, d, J=5.2 Hz), 7.91 (1H, t, J=5.6 Hz), 8.42 (1H, s). [M+H] Calc'd for C₂₅H₂₄N₄O₂, 413; Found, 413.

Preparation 116a: tert-butyl N-{[(4R)-7-(2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 83% yield from 2-methoxyphenylboronic acid and Preparation 18d according to the procedures for Preparation 43a. [M+H] Calc'd for C₂₂H₂₇NO₄, 370; Found, 370.

Preparation 116b: [(4R)-7-(2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in quantitative yield from Preparation 116a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₇H₁₉NO₂, 270; Found, 270.

Preparation 116c: methyl 3-({[(4R)-7-(2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 57% yield from Preparation 116b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₄N₂O₄, 405; Found, 405.

Example 116: 3-({[(4R)-7-(2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 75% yield from Preparation 116c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.90-1.93 (1H, m), 2.00-2.05 (1H, m), 3.15-3.18 (1H, m), 3.51-3.57 (1H, m), 3.72-3.76 (4H, m), 4.17-4.26 (2H, m), 6.87 (1H, s), 6.94-7.02 (2H, m), 7.09 (1H, d, J=8.0 Hz), 7.24-7.26 (1H, m), 7.30-7.35 (2H, m), 7.58 (1H, d, J=4.8 Hz), 7.86 (1H, d, J=5.2 Hz), 8.45 (1H, s). [M+H] Calc'd for C₂₃H₂₂N₂O₄, 391; Found, 391.

Preparation 117a: tert-butyl N-{[(4R)-7-[(3-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 55% yield from Preparation 18d and 3-cyano-N-methylaniline according to the general procedure for Preparation 9a. [M+H] Calc'd for C₂₃H₂₇N₃O₃, 394; Found, 394.

Preparation 117b: 3-{[(4R)-4-(aminomethyl)-3,4-dihydro-2H-1-benzopyran-7-yl](methyl)amino}benzonitrile

The title compound was prepared in quantitative yield from Preparation 117a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₈H₁₉N₃O, 294; Found, 294.

Preparation 117c: methyl 3-({[(4R)-7-[(3-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 56% yield from Preparation 117b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₅H₂₄N₄O₃, 429; Found, 429.

Example 117: 3-({[(4R)-7-[(3-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 85% yield from Preparation 117c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.88-1.98 (1H, m), 1.99-2.03 (1H, m), 3.11-3.15 (1H, m), 3.26 (3H, s), 3.49-3.54 (1H, m), 3.69-3.74 (1H, m), 4.15-4.25 (2H, m), 6.57 (1H, d, J=2.4 Hz), 6.65-6.68 (1H, m), 7.09-7.12 (1H, m), 7.18-7.20 (2H, m), 7.32-7.38 (2H, m), 7.57 (1H, d, J=5.2 Hz), 7.85 (1H, d, J=5.2 Hz), 8.41 (1H, s). [M+H] Calc'd for C₂₄H₂₂N₄O₃, 415; Found, 415.

Preparation 118a: tert-butyl N-{[(4R)-7-(4-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 60% yield from 4-fluoro-2-methoxyphenylboronic acid and Preparation 18d according to the procedures for Preparation 43a. [M+H] Calc'd for C₂₂H₂₆FNO₄, 388; Found, 388. [M+H] Calc'd for C₂₂H₂₆FNO₄, 388; Found, 388.

Preparation 118b: [(4R)-7-(4-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 95% yield from Preparation 118a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₇H₁₈FN₂O₄, 288; Found, 288.

Preparation 118c: methyl 3-({[(4R)-7-(4-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 63% yield from Preparation 118b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₃FN₂O₄, 423; Found, 423.

Example 118: 3-({[(4R)-7-(4-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 67% yield from Preparation 118c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.91-2.03 (2H, m), 3.15-3.18 (1H, m), 3.51-3.60 (1H, m), 3.72-3.77 (4H, m), 4.16-4.24 (2H, m), 6.80-6.85 (2H, m), 6.92 (1H, dd, J=1.6, 7.8 Hz), 6.99 (1H, dd, J=2.4, 11.2 Hz), 7.25-7.29 (1H, m), 3.34 (1H, d, J=8.0 Hz), 7.55 (1H, d, J=5.2 Hz), 7.87 (1H, d, J=5.2 Hz), 8.45 (1H, s). [M+H] Calc'd for C₂₃H₂₁FN₂O₄, 409; Found, 409.

Preparation 119a: tert-butyl N-{[(4R)-7-[(4-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 57% yield from Preparation 18d and 4-cyano-N-methylaniline according to the general procedure for Preparation 9a. [M+H] Calc'd for C₂₃H₂₇N₃O₃, 394; Found, 394.

Preparation 119b: 4-{[(4R)-4-(aminomethyl)-3,4-dihydro-2H-1-benzopyran-7-yl](methyl)amino}benzonitrile

The title compound was prepared in quantitative yield from Preparation 119a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₈H₁₉N₃O, 294; Found, 294.

Preparation 119c: methyl 3-({[(4R)-7-[(4-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 50% yield from Preparation 119b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₅H₂₄N₄O₃, 429; Found, 429.

Example 119: 3-({[(4R)-7-[(4-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 88% yield from Preparation 119c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.92-1.94 (1H, m), 2.01-2.04 (1H, m), 3.15-3.18 (1H, m), 3.27 (3H, s), 3.52-3.57 (1H, m), 3.72-3.76 (1H, m), 4.19-4.25 (2H, m), 6.67 (1H, d, J=2.0 Hz), 6.73-6.79 (3H, m), 7.39 (1H, d, J=8.0 Hz), 7.54-7.59 (3H, m), 7.86 (1H, d, J=5.2 Hz), 8.43 (1H, s). [M+H] Calc'd for C₂₄H₂₂N₄O₃, 415; Found, 415.

Preparation 120a: tert-butyl N-{[(1R)-6-[(cyclopropylmethyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a solution of Preparation 6d (0.5 g, 1.47 mmol) in toluene (10 mL) was added N-(cyclopropylmethyl)-N-methylamine hydrochloride (0.36 g, 2.94 mmol), Pd₂(dba)₃ (28 mg, 0.029 mmol), Xantphos (51 mg, 0.088 mmol) and Cs₂CO₃ (2.4 g, 7.35 mmol). The mixture was heated in a sealed tube at 130° C. for 4 h. The mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (PE:EtOAc=9:1 to 4:1) to give 48 mg (9%) of the title compound as a brown oil. [M+H] Calc'd for C₂₁H₃₂N₂O₂, 345; Found, 345.

Preparation 120b: (5R)-5-(aminomethyl)-N-(cyclopropylmethyl)-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in 90% yield from Preparation 120a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₆H₂₄N₂, 245; Found, 245.

Preparation 120c: methyl 3-({[(1R)-6-[(cyclopropylmethyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 38% yield from Preparation 120b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₃H₂₉N₃O₂, 380; Found, 380.

Example 120: 3-({[(1R)-6-[(cyclopropylmethyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 50% yield from Preparation 120c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 0.33-0.37 (2H, m), 0.60-0.65 (2H, m), 0.81-0.88 (1H, m), 1.80-1.87 (1H, m), 1.91-2.05 (3H, m), 2.83-2.98 (2H, m), 3.26 (3H, s), 3.30-3.32 (1H, m), 3.46 (2H, d, J=7.2 Hz), 3.59-3.68 (2H, m), 7.36-7.40 (2H, m), 7.53 (1H, d, J=8.4 Hz), 7.94 (1H, s) 8.19 (1H, d, J=5.2 Hz), 8.36 (1H, s). [M+H] Calc'd for C₂₂H₂₇N₃O₂, 366; Found, 366.

Preparation 121a: tert-butyl N-{[(1R)-6-[(6-methoxypyridin-2-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 58% yield from Preparation 6d and 6-methoxy-N-methylpyridin-2-amine according to the general procedure for Preparation 9a. [M+H] Calc'd for C₂₃H₃₁N₃O₃, 398; Found, 398.

Preparation 121b: N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-6-methoxy-N-methylpyridin-2-amine

The title compound was prepared in quantitative yield from Preparation 121a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₈H₂₃N₃O, 298; Found, 298.

Preparation 121c: methyl 3-({[(1R)-6-[(6-methoxypyridin-2-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 121b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₅H₂₈N₄O₃, 433; Found, 433.

Example 121: 3-({[(1R)-6-[(6-methoxypyridin-2-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 50% yield from Preparation 121c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.67-1.87 (4H, m), 2.70-2.74 (2H, m), 3.07-3.09 (1H, m), 3.34-3.36 (4H, m), 3.55-3.61 (1H, m), 3.80 (3H, s), 5.99-6.06 (2H, m), 7.03-7.07 (2H, m), 7.30-7.38 (2H, m), 7.57 (1H, d, J=4.8 Hz), 7.82 (1H, d, J=4.8 Hz), 8.54 (1H, s). [M+H] Calc'd for C₂₄H₂₆N₄O₃, 419; Found, 419.

Preparation 122a: methyl 3-({[(1R)-6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 6c (3.2 g, 13.39 mmol) in toluene (50 mL) was added methyl 3-bromo-isonicotinate (3.47 g, 16.07 mmol), Cs₂CO₃ (8.73 g, 26.78 mmol), Xantphos (462 mg, 0.8 mmol) and Pd₂(dba)₃ (250 mg, 0.27 mmol). The mixture was stirred overnight at 120° C. under nitrogen. The mixture was filtered and concentrated, and the residue was purified by prep-HPLC to give 2.53 g (50%) of the title compound as a yellow gum. [M+H] Calc'd for C₁₈H₁₉BrN₂O₂, 375, 377; Found, 375, 377.

Example 122: 3-({[(1R)-6-[methyl(5-methylpyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

To a solution of Preparation 122a (550 mg, 1.47 mmol) in toluene (10 mL) was added N,5-dimethylpyridin-2-amine (178 mg, 1.47 mmol), t-BuONa (282 mg, 2.94 mmol), JohnPhos (66 mg, 0.22 mmol) and Pd₂(dba)₃ (138 mg, 0.15 mmol). The mixture was stirred overnight at 110° C. under nitrogen. The mixture was filtered and concentrated, and the residue was purified by prep-HPLC to 101 mg (16%) as a yellow solid. (Hydrolysis of the ester had occurred during the course of this reaction.) ¹H NMR (300 MHz, DMSO-d₆): δ 1.64-1.70 (1H, m), 1.77-1.86 (3H, m), 2.10 (3H, s), 2.70-2.72 (2H, m), 3.07-3.11 (1H, m), 3.31 (3H, s), 3.40-3.48 (1H, m), 3.57-3.63 (1H, m), 6.45 (1H, d, J=8.4 Hz), 6.97 (1H, s), 7.00 (1H, d, J=1.5 Hz), 7.23 (1H, d, J=2.4 Hz), 7.32 (1H, d, J=8.1 Hz), 7.55 (1H, d, J=5.1 Hz), 7.81 (1H, d, J=4.8 Hz), 7.96 (1H, s), 8.33 (1H, s). [M+H] Calc'd for C₂₄H₂₆N₄O₂, 403; Found, 403.

Preparation 123a: tert-butyl N-{[(1R)-6-[methyl(6-methylpyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 30% yield from Preparation 6d and N,6-dimethylpyridin-2-amine according to the general procedure for Preparation 9a. [M+H] Calc'd for C₂₃H₃₁N₃O₂, 382; Found, 382.

Preparation 123b: N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N,6-dimethylpyridin-2-amine

The title compound was prepared in quantitative yield from Preparation 123a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₈H₂₃N₃, 282; Found, 282.

Preparation 123c: methyl 3-({[(1R)-6-[methyl(6-methylpyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 56% yield from Preparation 123b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₅H₂₈N₄O₂, 417; Found, 417.

Example 123: 3-({[(1R)-6-[methyl(6-methylpyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 35% yield from Preparation 123c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.67-1.70 (1H, m), 1.82-1.84 (3H, m), 2.34 (3H, s), 2.70-2.74 (2H, m), 3.07-3.09 (1H, m), 3.34-3.36 (4H, m), 3.53-3.58 (1H, m), 6.27 (1H, d, J=8.4 Hz), 6.49 (1H, d, J=7.2 Hz), 6.99-7.02 (2H, m), 7.27 (1H, dd, J=7.2, 8.0 Hz), 7.36 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=4.4 Hz), 7.60 (1H, d, J=4.8 Hz), 8.20 (1H, s). [M+H] Calc'd for C₂₄H₂₆N₄O₂, 403; Found, 403.

Preparation 124a: tert-butyl N-{[(4R)-7-(2-cyanophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 29% yield from Preparation 18d and 2-cyanophenylboronic acid according to the general procedure outlined for Preparation 43a. [M+H] Calc'd for C₂₂H₂₄N₂O₃, 365; Found, 365.

Preparation 124b: 2-[(4R)-4-(aminomethyl)-3,4-dihydro-2H-1-benzopyran-7-yl]benzonitrile

The title compound was prepared in quantitative yield from Preparation 124a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₇H₁₆N₂O, 265; Found, 265.

Preparation 124c: methyl 3-({[(4R)-7-(2-cyanophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 24% yield from Preparation 124b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₁N₃O₃, 400; Found, 400.

Example 124: 3-({[(4R)-7-(2-cyanophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 54% yield from Preparation 124c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.92-2.06 (2H, m), 3.21-3.26 (1H, m), 3.54-3.60 (1H, m), 3.76-3.81 (1H, m), 4.21-4.28 (2H, m), 6.99 (1H, d, J=1.6 Hz), 7.06-7.09 (1H, m), 7.50 (1H, d, J=8.4 Hz), 7.55-7.61 (3H, m), 7.75-7.79 (1H, m), 7.87 (1H, d, J=4.8 Hz), 7.93 (1H, d, J=6.4 Hz), 8.47 (1H, s). [M+H] Calc'd for C₂₃H₁₉N₃O₃, 386; Found, 386.

Preparation 125a: tert-butyl N-{[(1R)-6-[methyl(1-methyl-1H-pyrazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 62% yield from Preparation 6d and NJ-dimethyl-1H-pyrazol-3-amine according to the general procedure for Preparation 9a. [M+H] Calc'd for C₂₁H₃₀N₄O₂, 371; Found, 371.

Preparation 125b: N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N,1-dimethyl-1H-pyrazol-3-amine

The title compound was prepared in quantitative yield from Preparation 125a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₆H₂₂N₄, 271; Found, 271.

Preparation 125c: methyl 3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 24% yield from Preparation 125b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₃H₂₇N₅O₂, 406; Found, 406.

Example 125: 3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 90% yield from Preparation 125c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.62-1.82 (4H, m), 2.64-2.71 (2H, m), 3.00-3.05 (1H, m), 3.22 (3H, s), 3.37-3.44 (1H, m), 3.52-3.58 (1H, m), 3.72 (3H, s), 5.81 (1H, s), 6.81 (1H, s), 6.90 (1H, d, J=8.3 Hz), 7.17 (1H, d, J=8.3 Hz), 7.51 (1H, s), 7.57 (1H, br s), 7.83 (1H, br s), 8.35 (1H, br s). [M+H] Calc'd for C₂₂H₂₅N₅O₂, 392; Found, 392.

Preparation 126a: N-methyl-4-[2-(trimethylsilyl)ethynyl]aniline

To a suspension of 4-bromo-N-methylaniline (500 mg, 2.7 mmol), trimethylsilyl acetylene (527 mg, 5.4 mmol), CuI (92 mg, 0.5 mmol) and PPh₃ (233 mg, 0.9 mmol) in TEA (20 mL) was added PdCl₂(PPh₃)₂ (94 mg, 0.1 mmol) at r.t. under N₂. The reaction was stirred at reflux overnight. The reaction was filtered, concentrated, and purified by silica gel chromatography (PE:EtOAc=20:1) to give 200 mg (37%) of the title compound as a yellow oil. [M+H] Calc'd for C₁₂H₁₇NSi, 204; Found, 204.

Preparation 126b: methyl 3-({[(4R)-7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared from Preparation 18c and methyl 3-bromo-isonicotinate according to the general procedure outline for Preparation 122a. [M+H] Calc'd for C₁₇H₁₇BrN₂O₃, 377, 379; Found, 377, 379.

Preparation 126c: methyl 3-({[(4R)-7-[methyl({4-[2-(trimethylsilyl)ethynyl]phenyl})amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a suspension of Preparation 126b (100 mg, 0.27 mmol), N-methyl-4-[2-(trimethylsilyl)-ethynyl]aniline (54 mg, 0.27 mmol), Xantphos (23 mg, 0.04 mmol) and Cs₂CO₃ (123 mg, 0.38 mmol) in toluene (10 mL) was added Pd₂dba₃ (12 mg, 0.01 mmol) at r.t. under N₂. The reaction was stirred at 110° C. overnight. The reaction was filtered, concentrated, and purified by silica gel chromatography (PE:EtOAc=5:1) to give 30 mg (23%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₉H₃₃N₃O₃Si, 500; Found, 500.

Preparation 126d: methyl 3-({[(4R)-7-[(4-ethynylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 126c (50 mg, 0.10 mmol) in THF (5 mL) was added TBAF (0.20 mL, 1.0 M in THF, 0.20 mmol), and the reaction was stirred at r.t. for 1 h. The solution was concentrated and dried under vacuum. This material was used for the next step directly without purification. [M+H] Calc'd for C₂₆H₂₅N₃O₃, 428; Found, 428.

Example 126: 3-({[(4R)-7-[(4-ethynylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 49% yield from Preparation 126d according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.83-1.88 (1H, m), 1.94-2.03 (1H, m), 3.09-3.12 (1H, m), 3.19 (3H, s), 3.49-3.51 (1H, m), 3.67-3.72 (1H, m), 3.94 (1H, s), 4.17-4.21 (2H, m), 6.55 (1H, d, J=1.8 Hz), 6.63 (1H, dd, J=1.8, 8.1 Hz), 6.80 (2H, d, J=8.7 Hz), 7.28-7.31 (3H, m), 7.57 (1H, d, J=4.8 Hz), 7.84 (1H, d, J=5.1 Hz), 8.40 (1H, s). [M+H] Calc'd for C₂₅H₂₃N₃O₃, 414; Found, 414.

Preparation 127a: N-methyl-1,3-dihydro-2-benzofuran-5-amine

1,3-Dihydro-2-benzofuran-5-amine (300 mg, 2.2 mmol) was added to HCOOH (10 mL), and the reaction was stirred at reflux overnight. The reaction was concentrated, basified to pH=8 with sat Na₂CO₃, and extracted with EtOAc. Organics were washed with brine, dried (Na₂SO₄), and concentrated to give 250 mg (69%) of N-(1,3-dihydro-2-benzofuran-5-yl)formamide as a yellow oil.

To a solution of N-(1,3-dihydro-2-benzofuran-5-yl)formamide (250 mg, 1.5 mmol) in THF (20 mL) was added LAH (1.9 mL, 2.4 M in THF, 4.6 mmol) at 0° C. The reaction was stirred at r.t. for 2 h. The solution was diluted with water (0.5 mL) and EtOAc (30 mL), dried (Na₂SO₄), and concentrated to give 220 mg (96%) of the title compound as a yellow oil. [M+H] Calc'd for C₉H_(ii)NO, 150; Found, 150.

Preparation 127b: methyl 3-({[(4R)-7-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 40% yield from Preparation 126b and N-methyl-1,3-dihydro-2-benzofuran-5-amine according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₆H₂₇N₃O₄, 446; Found, 446.

Example 127: 3-({[(4R)-7-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 90% yield from Preparation 127b according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.84-1.87 (1H, m), 1.96-1.99 (1H, m), 3.04-3.08 (1H, m), 3.19 (3H, s), 3.44-3.50 (1H, m), 3.64-3.69 (1H, m), 4.10-4.18 (2H, m), 4.95 (4H, s), 6.32 (1H, d, J=2.8 Hz), 6.45 (1H, dd, J=2.4, 8.4 Hz), 6.91-6.97 (2H, m), 7.16-7.22 (2H, m), 7.57 (1H, d, J=4.8 Hz), 7.84 (1H, d, J=5.2 Hz), 8.40 (1H, s). [M+H] Calc'd for C₂₅H₂₅N₃O₄, 432; Found, 432.

Preparation 128a: tert-butyl N-{[(4R)-7-{methyl[4-(trifluoromethyl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 23% yield from Preparation 18d and N-methyl-4-(trifluoromethyl)aniline according to the general procedure outlined for Preparation 9a. [M+H] Calc'd for C₂₃H₂₇F₃N₂O₃, 437; Found, 437.

Preparation 128b: (4R)-4-(aminomethyl)-N-methyl-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 95% yield from Preparation 128a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₈H₁₉F₃N₂O, 337; Found, 337.

Preparation 128c: methyl 3-({[(4R)-7-{methyl[4-(trifluoromethyl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 60% yield from Preparation 128b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₅H₂₄F₃N₃O₃, 472; Found, 472.

Preparation 128: 3-({[(4R)-7-{methyl[4-(trifluoromethyl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 16% yield from Preparation 128c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.88-1.92 (1H, m), 1.96-2.05 (1H, m), 3.13-3.18 (1H, m), 3.37 (3H, s), 3.51-3.56 (1H, m), 3.71-3.76 (1H, m), 4.15-4.27 (2H, m), 6.64 (1H, s), 6.71-6.74 (1H, m), 6.88 (2H, d, J=8.4 Hz), 7.37-7.34 (1H, m), 7.48 (2H, d, J=8.8 Hz), 7.58 (1H, d, J=4.8 Hz), 7.85 (1H, d, J=5.2 Hz), 8.43 (1H, s). [M+H] Calc'd for C₂₄H₂₂F₃N₃O₃, 458; Found, 458.

Preparation 129a: N-(2,2,2-trifluoroethyl)aniline

To a solution of aniline (10.0 g, 107 mmol) in DCM (50 mL) was added TFAA (24.8 g, 118 mmol) and TEA (22 mL, 160 mmol). The mixture was stirred at r.t. for 2 h. The reaction was washed with water, dried (Na₂SO₄), and concentrated to give 17.7 g (87%) of 2,2,2-trifluoro-N-phenylacetamide as a white solid.

To a solution of 2,2,2-trifluoro-N-phenylacetamide (5.0 g, 26 mmol) in THF (10 mL) was added BH₃ in THF (130 mL, 130 mmol, 1.0 M). The resulting mixture was refluxed overnight. The mixture was quenched with water and methanol, concentrated to remove most of THF, and extracted with EtOAc. Organics were washed with brine, dried (Na₂SO₄), and concentrated to give 4.17 g (92%) of the title compound as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 3.71-3.75 (2H, m), 6.66 (2H, d, J=8.0 Hz), 6.79 (1H, t, J=7.2 Hz), 7.20 (2H, t, J=8.0 Hz).

Preparation 129b: methyl 3-[({7-[phenyl(2,2,2-trifluoroethyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)amino]pyridine-4-carboxylate

The title compound was prepared in 4% yield from Preparation 14c and Preparation 129a according to the general procedure for Preparation 15a. [M+H] Calc'd for C₂₅H₂₆F₃N₃O₃, 472; Found, 472.

Example 129: 3-[({7-[phenyl(2,2,2-trifluoroethyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)amino]pyridine-4-carboxylic Acid

The title compound was prepared in 44% yield from Preparation 129b according to the procedure for Example 1. ¹H NMR (400 MHz, MeOD-d₄): δ 1.90-1.95 (1H, m), 2.05-2.11 (1H, m), 3.08-3.12 (1H, m), 3.43-3.48 (1H, m), 3.58-3.63 (1H, m), 4.06-4.14 (1H, m), 4.24-4.30 (1H, m), 5.24 (2H, t, J=4.6 Hz), 6.29 (1H, d, J=3.2 Hz), 6.36 (1H, d, J=6.0 Hz), 6.92-6.98 (3H, m), 7.04 (1H, d, J=8.1 Hz), 7.18-7.22 (2H, m), 7.80-7.82 (1H, m), 8.03-8.05 (1H, m), 8.23 (1H, d, J=2.0 Hz). [M+H] Calc'd for C₂₄H₂₂F₃N₃O₃, 458; Found, 458.

Preparation 130a: tert-butyl N-({7-[benzyl(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)carbamate

To a solution of tert-butyl N-[(7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]carbamate (500 mg, 1.46 mmol) in toluene (10 mL) was added N-methyl-benzylamine (212 mg, 1.75 mmol), Cs₂CO₃ (950 mg, 2.92 mmol), BINAP (44 mg, 0.07 mmol) and Pd(OAc)₂ (16 mg, 0.07 mmol). The mixture was stirred overnight at 100° C. under nitrogen. The mixture was filtered and concentrated, and the residue was purified by prep-HPLC to give 362 mg (65%) of the title compound as a colorless gum. [M+H] Calc'd for C₂₃H₃₀N₂O₃, 383; Found, 383.

Preparation 130b: 4-(aminomethyl)-N-benzyl-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 97% yield from Preparation 130a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₈H₂₂N₂O, 283; Found, 283.

Preparation 130c: methyl 3-({[(1R)-6-[benzyl(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 4% yield from Preparation 130b according to the general procedure for Preparation 1e. [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Example 130: 3-({[(1R)-6-[benzyl(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 76% yield from Preparation 130c according to the procedure for Example 1. ¹H NMR (400 MHz, MeOD-d₄): δ 1.84-1.93 (1H, m), 2.00-2.09 (1H, m), 3.04 (3H, s), 3.10-3.15 (1H, m), 3.44-3.50 (1H, m), 3.57-3.62 (1H, m), 4.08-4.18 (2H, m), 4.51 (2H, s), 6.47 (1H, d, J=2.0 Hz), 6.53 (1H, d, J=6.0 Hz), 7.12-7.14 (3H, m), 7.20-7.22 (3H, m), 7.84 (1H, s), 8.15 (1H, d, J=4.4 Hz), 8.29 (1H, m). [M+H] Calc'd for C₂₄H₂₅N₃O₃, 404; Found, 404.

Preparation 131a: N-methyl-2,3-dihydro-1H-inden-5-amine

The title compound was prepared in 16% overall yield from 2,3-dihydro-1H-inden-5-amine according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₁₀H₁₃N, 148; Found, 148.

Preparation 131b: tert-butyl N-{[(4R)-7-[(2,3-dihydro-1H-inden-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 73% yield from Preparation 18d and Preparation 131a according to the general procedure outlined for Preparation 6e. [M+H] Calc'd for C₂₅H₃₂N₂O₃, 409; Found, 409.

Preparation 131c: (4R)-4-(aminomethyl)-N-(2,3-dihydro-1H-inden-5-yl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 98% yield from Preparation 131b according to the procedure for Preparation 43b. [M+H] Calc'd for C₂₀H₂₄N₂O, 309; Found, 309.

Preparation 131d: methyl 3-({[(4R)-7-[(2,3-dihydro-1H-inden-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 51% yield from Preparation 131c according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₇H₂₉N₃O₃, 444; Found, 444.

Example 131: 3-({[(4R)-7-[(2,3-dihydro-1H-inden-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 24% yield from Preparation 131d according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.84-1.85 (1H, m), 1.95-2.05 (3H, m), 2.79-2.83 (4H, m), 3.03-3.05 (1H, m), 3.15 (3H, s), 3.43-3.48 (1H, m), 3.62-3.66 (1H, m), 4.09-4.16 (2H, m), 6.20 (1H, d, J=2.4 Hz), 6.35 (1H, d, J=6.0 Hz), 6.81 (1H, d, J=6.0 Hz), 6.94 (1H, s), 7.09-7.16 (2H, m), 7.59 (1H, d, J=5.2 Hz), 7.84 (1H, d, J=4.8 Hz), 8.40 (1H, s). [M+H] Calc'd for C₂₆H₂₇N₃O₃, 430; Found, 430.

Preparation 132a: tert-butyl N-{[(1R)-6-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 48% yield from Preparation 18d and Preparation 127a according to the general procedure outlined for Preparation 9a. [M+H] Calc'd for C₂₅H₃₂N₂O₃, 409; Found, 409.

Preparation 132b: N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-methyl-1,3-dihydro-2-benzofuran-5-amine

The title compound was prepared in quantitative yield from Preparation 132a according to the procedure for Preparation 43b. [M+H] Calc'd for C₂₀H₂₄N₂O, 309; Found, 309.

Preparation 132c: methyl 3-({[(1R)-6-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 60% yield from Preparation 132b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₇H₂₉N₃O₃, 444; Found, 444.

Example 132: 3-({[(1R)-6-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 84% yield from Preparation 132c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.65-1.84 (4H, m), 2.64-2.68 (2H, m), 3.03-3.06 (1H, m), 3.21 (3H, s), 3.40-3.46 (1H, m), 3.55-3.60 (1H, m), 4.93 (4H, s), 6.74-6.78 (2H, m), 6.84-6.89 (2H, m), 7.15-7.23 (2H, m), 7.56 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=5.2 Hz), 8.34 (1H, s). [M+H] Calc'd for C₂₆H₂₇N₃O₃, 430; Found, 430.

Preparation 133a: methyl 3-({[(1R)-6-[cyclopentyl(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a suspension of Preparation 14a (300 mg, 0.80 mmol), N-methylcyclopentanamine (87 mg, 0.88 mmol), Xantphos (69 mg, 0.12 mmol) and Cs₂CO₃ (365 mg, 1.12 mmol) in toluene (20 mL) was added Pd₂dba₃ (37 mg, 0.04 mmol) at r.t. under N₂. The reaction was stirred at 110° C. overnight. The reaction was filtered, concentrated, and purified by silica gel chromatography (PE:EtOAc=5:1) to give 20 mg (6%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₃H₂₉FN₃O₃, 396; Found, 396.

Example 133: 3-({[(1R)-6-[cyclopentyl(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 48% yield from Preparation 133a according to the procedure for Example 1. ¹H NMR (300 MHz, CD₃OD): δ 1.32-1.34 (2H, m), 1.68-1.72 (3H, m), 1.84-1.87 (3H, m), 2.06-2.11 (1H, m), 2.20-2.22 (1H, m), 3.28 (3H, s), 3.34-3.40 (1H, m), 3.66-3.71 (1H, m), 3.79-3.84 (1H, m), 4.16-4.19 (1H, m), 4.33-4.38 (2H, m), 7.16-7.18 (2H, m), 7.76 (1H, d, J=5.7 Hz), 8.02 (1H, d, J=4.2 Hz), 8.32 (1H, d, J=4.2 Hz), 8.50 (1H, s). [M+H] Calc'd for C₂₂H₂₇FN₃O₃, 382; Found, 382.

Preparation 134a: 4-cyclopropyl-N-methylaniline

To a suspension of 4-bromo-N-methylaniline (500 mg, 2.69 mmol), cyclopropylboronic acid (462 mg, 5.38 mmol), (cyclohexyl)₃P⁺HBF₄ ⁻ (99 mg, 0.27 mmol) and K₃PO₄ (2.0 g, 9.4 mmol) in toluene (20 mL) and H₂O (1 mL) was added Pd(OAc)₂ (36 mg, 0.16 mmol) at r.t. under N₂. The reaction was stirred at reflux overnight. The reaction was filtered, concentrated, and purified by silica gel chromatography (PE:EtOAc=10:1) to give 268 mg (68%) of the title compound as a brown oil. [M+H] Calc'd for C₁₀H₂₃N, 148; Found, 148.

Preparation 134b: methyl 3-({[(4R)-7-[(4-cyclopropylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 4% yield from Preparation 126b and 4-cyclopropyl-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₂₉N₃O₃, 444; Found, 444.

Example 134: 3-({[(4R)-7-[(4-cyclopropylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 28% yield from Preparation 134b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 0.60-0.63 (2H, m), 0.88-0.92 (2H, m), 1.85-1.89 (3H, m), 3.03-3.05 (1H, m), 3.19 (3H, s), 3.45-3.48 (1H, m), 3.62-3.66 (1H, m), 4.10-4.16 (2H, m), 6.24 (1H, d, J=2.4 Hz), 6.24-6.39 (1H, m), 6.93-7.03 (4H, m), 7.12 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=5.2 Hz), 7.84 (1H, d, J=5.2 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₆H₂₇N₃O₃, 430; Found, 430.

Preparation 135a: N-methyl-1-benzofuran-6-amine

A mixture of 6-bromo-1-benzofuran (1.0 g, 5.1 mmol), methylamine (2N, 25 mL, 50 mmol), CuI (1.16 g, 6.1 mmol) and KOAc (1.25 g, 12.7 mmol) in DMF (10 mL) was stirred overnight at 100° C. under nitrogen in a sealed tube. The mixture was cooled to r.t., diluted with aqueous ammonium hydroxide, and extracted with EtOAc. The organic layer was concentrated, and the residue was purified by silica gel chromatography to give 250 mg (33%) of the title compound as a yellow oil. [M+H] Calc'd for C₉H₉NO, 148; Found, 148.

Preparation 135b: tert-butyl N-{[(1R)-6-[(1-benzofuran-6-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 61% yield from Preparation 6d and Preparation 135a according to the general procedure outlined for Preparation 6e. [M+H] Calc'd for C₂₅H₃₀N₂O, 407; Found, 407.

Preparation 135c: N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-methyl-1-benzofuran-6-amine

The title compound was prepared in 95% yield from Preparation 135b according to the procedure for Preparation 43b. [M+H] Calc'd for C₂₀H₂₂N₂O, 307; Found, 307.

Preparation 135d: methyl 3-({[(1R)-6-[(1-benzofuran-6-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 50% yield from Preparation 135c according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₇H₂₇N₃O₃, 442; Found, 442.

Example 135: 3-({[(1R)-6-[(1-benzofuran-6-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 43% yield from Preparation 135d according to the procedure for Example 1. ¹H NMR (400 MHz, MeOD-d₄): δ 1.73-1.96 (4H, m), 2.69-2.76 (2H, m), 3.11-3.16 (1H, m), 3.28 (3H, s), 3.36-3.60 (2H, m), 6.10 (1H, s), 6.73-6.79 (3H, m), 6.90 (1H, d, J=8.4 Hz), 7.08 (1H, s), 7.16 (1H, d, J=8.2 Hz), 7.42 (1H, d, J=8.4 Hz), 7.62 (1H, s), 7.78-7.83 (2H, m), 8.15 (1H, s). [M+H] Calc'd for C₂₆H₂₆N₃O₃, 428; Found, 428.

Preparation 136a: N-methyl-1-benzofuran-5-amine

The title compound was prepared in 76% overall yield from 1-benzofuran-5-amine according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₉H₉NO, 148; Found, 148.

Preparation 136b: tert-butyl N-{[(4R)-7-[(1-benzofuran-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 14% yield from Preparation 18d and Preparation 136a according to the general procedure outlined for Preparation 6e. [M+H] Calc'd for C₂₄H₂₈N₂O₄, 409; Found, 409.

Preparation 136c: (4R)-4-(aminomethyl)-N-(1-benzofuran-5-yl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 75% yield from Preparation 136b according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₉H₂₀N₂O₂, 309; Found, 309.

Preparation 136d: methyl 3-({[(4R)-7-[(1-benzofuran-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 53% yield from Preparation 136c according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₆H₂₅N₃O₄, 444; Found, 444.

Example 136: 3-({[(4R)-7-[(1-benzofuran-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 50% yield from Preparation 136d according to the procedure for Example 1. ¹H NMR (400 MHz, MeOD-d₄): δ 1.83-1.88 (1H, m), 1.99-2.09 (1H, m), 3.03-3.06 (1H, m), 3.14 (3H, s), 3.41-3.47 (1H, m), 3.55-3.60 (1H, m), 4.02-4.14 (2H, m), 6.10 (1H, s), 6.17 (1H, d, J=5.6 Hz), 6.69 (1H, s), 6.90-6.95 (2H, m), 7.25 (1H, s), 7.34 (1H, d, J=8.4 Hz), 7.63 (1H, s), 7.81 (1H, s), 8.13 (1H, d, J=5.6 Hz), 8.22 (1H, s). [M+H] Calc'd for C₂₅H₂₃N₃O₄, 430; Found, 430.

Preparation 137a: methyl 3-({[(1R)-6-[(1-benzofuran-5-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 15% yield from Preparation 122a and Preparation 136a according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₂₇N₃O₃, 442; Found, 442.

Example 137: 3-({[(1R)-6-[(1-benzofuran-5-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 23% yield from Preparation 137a according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.76-1.79 (1H, m), 1.86-2.06 (3H, m), 2.70-2.75 (2H, m), 3.13-3.17 (1H, m), 3.28 (3H, s), 3.51-3.63 (2H, m), 6.60 (2H, s), 6.80 (1H, s), 7.02-7.09 (2H, m), 7.33 (1H, s), 7.44 (1H, d, J=8.4 Hz), 7.90 (1H, s), 7.75 (1H, s), 8.18 (1H, d, J=2.0 Hz), 8.26 (1H, s). [M+H] Calc'd for C₂₆H₂₅N₃O₃, 428; Found, 428.

Preparation 138a: methyl 3-({[(4R)-7-(2-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 126b (180 mg, 0.48 mmol) in DMF (5 mL) was added 2-hydroxyphenylboronic acid (80 mg, 0.57 mmol), K₂CO₃ (133 mg, 0.96 mmol) and Pd(PPh₃)₄ (58 mg, 0.05 mmol). The mixture was stirred for 4 h at 105° C. under nitrogen. The mixture was cooled, diluted with water, and extracted with EtOAc. Organics were washed with brine, dried (Na₂SO₄), and concentrated to give 147 mg (79%) of the title compound as a yellow solid. [M+H] Calc'd for C₂₃H₂₂N₂O₄, 391; Found, 391.

Example 138: 3-({[(4R)-7-(2-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 40% yield from Preparation 138a according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.92-1.93 (1H, m), 1.98-2.03 (1H, m), 3.14-3.17 (1H, m), 3.50-3.56 (1H, m), 3.71-3.75 (1H, m), 4.17-4.23 (2H, m), 6.82-7.22 (6H, m), 7.31 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=4.8 Hz), 7.85 (1H, d, J=5.2 Hz), 8.44 (1H, s), 9.44 (1H, s).

[M+H] Calc'd for C₂₂H₂₀N₂O₄, 377; Found, 377.

Preparation 139a: tert-butyl N-{[(1R)-6-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

Preparation 6d (300 mg, 0.88 mmol), CuI (201 mg, 1.06 mmol), KOAc (216 mg, 2.2 mmol), and CuOAc (176 mg, 0.88 mmol) were combined in DMF (3 mL) in a microwave tube. Methylamine (0.7 mL, 40% in water, 8.8 mmol) was added, and the reaction stirred at 100° C. in the microwave for 2 h. The reaction was diluted with EtOAc, washed with water and brine, dried (MgSO₄), and concentrated. The residue was purified by silica gel chromatography (20% to 80% EtOAc/hexanes) to give 186 mg (73%) of the title compound as a yellow oil. [M+H] Calc'd for C₁₇H₂₆N₂O₂, 291; Found, 291.

Preparation 139b: tert-butyl N-{[(1R)-6-[methyl(2-methyl-1,3-thiazol-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a suspension of Preparation 139a (200 mg, 0.69 mmol), 4-bromo-2-methyl-1,3-thiazole (184 mg, 1.03 mmol), Xantphos (60 mg, 0.10 mmol) and Cs₂CO₃ (315 mg, 0.97 mmol) in toluene (20 mL) was added Pd₂dba₃ (32 mg, 0.04 mmol) at r.t. under N₂. The reaction was stirred at reflux overnight. The reaction was cooled, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=3:1) to give 60 mg (23%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₁H₂₉N₃O₂S, 388; Found, 388.

Preparation 139c: N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N,2-dimethyl-1,3-thiazol-4-amine

The title compound was prepared in quantitative yield from Preparation 136b according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₆H₂₁N₃S, 288; Found, 288.

Preparation 139d: methyl 3-({[(1R)-6-[methyl(2-methyl-1,3-thiazol-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 23% yield from Preparation 139c according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₃H₂₆N₄O₂S, 423; Found, 423.

Example 139: 3-({[(1R)-6-[methyl(2-methyl-1,3-thiazol-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 63% yield from Preparation 139d according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.651.69 (1H, m), 1.81-1.85 (3H, m), 2.57 (3H, s), 2.67-2.70 (2H, m), 3.05-3.07 (1H, m), 3.25 (3H, s), 3.42-3.45 (1H, m), 3.55-3.60 (1H, m), 6.32 (1H, s), 6.84 (1H, d, J=2.8 Hz), 6.90 (1H, dd, J=2.4, 8.4 Hz), 7.21 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=4.4 Hz), 7.83 (1H, d, J=5.2 Hz), 8.36 (1H, s). [M+H] Calc'd for C₂₂H₂₄N₄O₂S, 409; Found, 409.

Preparation 140a: tert-butyl N-{[(1R)-6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 38% yield from Preparation 6d and N,4-dimethylaniline according to the general procedure outlined for Preparation 9a. [M+H] Calc'd for C₂₆H₃₂N₂O₂, 381; Found, 381.

Preparation 140b: (5R)-5-(aminomethyl)-N-methyl-N-(4-methylphenyl)-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation 140a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₉H₂₄N₂, 281; Found, 281.

Preparation 140c: methyl 3-({[(1R)-6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 76% yield from Preparation 140b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₆H₂₉N₃O₂, 416; Found, 416.

Example 140: 3-({[(1R)-6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 98% yield from Preparation 140c according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.63-1.81 (4H, m), 2.24 (3H, s), 2.64-2.65 (2H, m), 2.99-3.05 (1H, m), 3.18 (3H, s), 3.38-3.42 (1H, m), 3.53-3.59 (1H, m), 6.66-6.71 (2H, m), 6.88-6.90 (2H, m), 7.09 (2H, d, J=2.4 Hz), 7.17 (1H, d, J=8.1 Hz), 7.55 (1H, d, J=5.1 Hz), 7.82 (1H, d, J=5.1 Hz), 8.34 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₂, 402; Found, 402.

Preparation 141a: methyl 3-({[(4R)-7-[(1-benzofuran-6-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 135a (250 mg, 1.71 mmol) in toluene (10 mL) was added Preparation 126b (536 mg, 1.42 mmol), Cs₂CO₃ (926 mg, 2.84 mmol), BINAP (44 mg, 0.07 mmol) and Pd(OAc)₂ (16 mg, 0.07 mmol). The mixture was stirred overnight at 120° C. under nitrogen. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography to give 160 mg (25%) of the title compound as a white solid. [M+H] Calc'd for C₂₆H₂₅N₃O₄, 444; Found, 444.

Example 141: 3-({[(4R)-7-[(1-benzofuran-6-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 40% yield from Preparation 141a according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.83-1.87 (1H, m), 1.96-2.00 (1H, m), 3.05-3.08 (1H, m), 3.24 (3H, s), 3.46-3.51 (1H, m), 3.64-3.69 (1H, m), 4.10-4.20 (2H, m), 6.33 (1H, s), 6.45 (1H, d, J=6.0 Hz), 6.88 (1H, s), 6.94 (1H, d, J=6.8 Hz), 7.15 (1H, d, J=8.4 Hz), 7.25 (1H, s), 7.51 (1H, d, J=8.8 Hz), 7.62 (1H, d, J=4.8 Hz), 7.86-7.89 (2H, m), 8.41 (1H, s). [M+H] Calc'd for C₂₅H₂₃N₃O₄, 430; Found, 430.

Preparation 142a: methyl 3-[(3,4-dihydro-1H-2-benzopyran-1-ylmethyl)amino]pyridine-4-carboxylate

The title compound was prepared in 70% yield from 3,4-dihydro-1H-2-benzopyran-1-ylmethanamine according to the procedure for Preparation 4d. ¹H NMR (400 MHz, CDCl₃): δ 2.72-2.78 (1H, m), 3.00-3.09 (1H, m), 3.53-3.60 (1H, m), 3.78-3.87 (5H, m), 4.18-4.24 (1H, m), 5.07 (1H, d, J=6.4 Hz), 7.15-7.22 (4H, m), 7.60 (1H, d, J=5.0 Hz), 7.72 (1H, br s), 7.91 (1H, d, J=5.0 Hz), 8.31 (1H, s). [M+H] Calc'd for C₁₇H₁₈N₂O₃, 299; Found, 299.

Example 142: 3-[(3,4-dihydro-1H-2-benzopyran-1-ylmethyl)amino]pyridine-4-carboxylic Acid

The title compound was prepared in 53% yield from Preparation 142a according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 2.69-2.74 (1H, m), 2.86-2.94 (1H, m), 3.54-3.60 (1H, m), 3.71-3.85 (2H, m), 4.08-4.12 (1H, m), 4.98 (1H, d, J=5.8 Hz), 7.16-7.21 (3H, m), 7.34 (1H, d, J=4.2 Hz), 7.52 (1H, d, J=4.8 Hz), 7.81 (1H, d, J=4.8 Hz), 7.90 (1H, br s), 8.34 (1H, s), 12.52 (1H, br s). [M+H] Calc'd for C₁₆H₁₆N₂O₃, 285; Found, 285.

Example 143: 3-({[(1R)-6-[methyl(3-methylphenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

To a solution of Preparation 122a (374 mg, 1.0 mmol) in toluene (10 mL) was added N,3-dimethylaniline (242 mg, 2.0 mmol), t-BuONa (192 mg, 2.0 mmol), JohnPhos (45 mg, 0.15 mmol) and Pd₂(dba)₃ (92 mg, 0.1 mmol). The mixture was refluxed for 3 h under N₂. The reaction was cooled, filtered and concentrated. The residue was purified by prep-HPLC to give 21 mg (5%) of the title compound as a yellow solid. (Ester hydrolysis occurred during the course of the reaction.) ¹H NMR (300 MHz, MeOD-d₄): δ 1.76-1.80 (1H, m), 1.83-2.02 (3H, m), 2.26 (3H, s), 2.71-2.75 (2H, m), 3.15-3.19 (1H, m), 3.22 (3H, s), 3.56-3.60 (2H, m), 6.73-6.78 (5H, m), 7.08-7.16 (2H, m), 7.89-7.91 (1H, m), 8.21 (1H, d, J=5.4 Hz), 8.29 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₂, 402; Found, 402.

Preparation 144a: tert-butyl N-{[(1R)-6-[methyl(thiophen-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a suspension of Preparation 139a (50 mg, 0.17 mmol), 2-bromo-thiophene (56 mg, 0.34 mmol), JohnPhos (8 mg, 0.03 mmol) and t-BuONa (33 mg, 0.34 mmol) in toluene (10 mL) was added Pd₂dba₃ (16 mg, 0.02 mmol) at r.t. under N₂. The reaction was stirred at reflux overnight. The reaction was cooled, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=8:1) to give 40 mg (63%) of the title compound as a yellow oil.

[M+H] Calc'd for C₂₁H₂₈N₂O₂S, 373; Found, 373.

Preparation 144b: N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-methylthiophen-2-amine

The title compound was prepared in quantitative yield from Preparation 144a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₆H₂₀N₂S, 273; Found, 273.

Preparation 144c: methyl 3-({[(1R)-6-[methyl(thiophen-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 22% yield from Preparation 144b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₃H₂₅N₃O₂S, 408; Found, 408.

Example 144: 3-({[(1R)-6-[methyl(thiophen-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 53% yield from Preparation 144c according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.59-1.64 (1H, m), 1.76-1.84 (3H, m), 2.65-2.69 (2H, m), 2.98-3.05 (1H, m), 3.23 (3H, s), 3.41-3.43 (1H, m), 3.51-3.57 (1H, m), 6.59 (1H, d, J=2.7 Hz), 6.75-6.78 (2H, m), 6.88 (1H, dd, J=3.9, 5.1 Hz), 7.03 (1H, dd, J=0.6, 5.1 Hz), 7.19 (1H, d, J=8.1 Hz), 7.55 (1H, d, J=4.2 Hz), 7.83 (1H, d, J=4.5 Hz), 8.34 (1H, s). [M+H] Calc'd for C₂₂H₂₃N₃O₂S, 394; Found, 394.

Preparation 145a: tert-butyl N-{[(4R)-7-[methyl(5-methylpyridin-2-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 9% yield from Preparation 18d and N,5-dimethylpyridin-2-amine according to the general procedure outlined for Preparation 6e. [M+H] Calc'd for C₂₂H₂₉N₃O₃, 384; Found, 384.

Preparation 145b: N-[(4R)-4-(aminomethyl)-3,4-dihydro-2H-1-benzopyran-7-yl]-N,5-dimethylpyridin-2-amine

The title compound was prepared in quantitative yield from Preparation 145a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₇H₂₁N₃O, 284; Found, 284.

Preparation 145c: methyl 3-({[(4R)-7-[methyl(5-methylpyridin-2-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 78% yield from Preparation 145b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₆N₄O₃, 419; Found, 419.

Example 145: 3-({[(4R)-7-[methyl(5-methylpyridin-2-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 65% yield from Preparation 145c according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.88-1.91 (1H, m), 1.96-2.03 (1H, m), 2.14 (3H, s), 3.10-3.14 (1H, m), 3.25 (3H, s), 3.43-3.55 (1H, m), 3.68-3.74 (1H, m), 4.13-4.21 (2H, m), 6.52 (1H, d, J=8.4 Hz), 6.63 (1H, s), 6.72 (1H, d, J=8.1 Hz), 7.26-7.32 (2H, m), 7.56 (1H, d, J=5.1 Hz), 7.84 (1H, d, J=6.9 Hz), 7.98 (1H, s), 8.41 (1H, s). [M+H] Calc'd for C₂₃H₂₄N₄O₃, 405; Found, 405.

Preparation 146a: 2-{3-[methyl(phenyl)amino]phenyl}ethan-1-ol

1-Bromo-3-[2-(tert-butyldimethylsilyloxy)ethyl]benzene (2.5 g, 7.96 mmol), N-methylaniline (1.02 g, 9.55 mmol), Pd₂dba₃ (364 mg, 0.4 mmol), Xantphos (691 mg, 1.19 mmol) and NaOtBu (727 mg, 9.55 mmol) were combined in toluene (12 mL), and the reaction was heated at 100° C. in the microwave for 90 min. The reaction was diluted with EtOAc, washed with brine, dried (MgSO₄), and concentrated. The residue was stirred in 70% TFA/DCM (10 mL) for 2 h. The solution was concentrated and purified by silica gel chromatography (30% to 100% EtOAc/hexanes) to give 1.3 g (72%) of the title compound as a clear oil. ¹H NMR (400 MHz, CDCl₃): δ 1.53 (1H, br s), 2.81 (2H, t, J=6.5 Hz), 3.31 (3H, s), 3.83 (2H, t, J=6.5 Hz), 6.81 (1H, d, J=7.4 Hz), 6.86-6.89 (2H, m), 6.97 (1H, t, J=7.3 Hz), 7.04 (d, 2H, J=7.8 Hz), 7.18-7.29 (3H, m). [M+H] Calc'd for C₁₅H₁₇NO, 228; Found, 228.

Preparation 146b: 1-(aminomethyl)-N-methyl-N-phenyl-3,4-dihydro-1H-2-benzopyran-6-amine

2-{3-[Methyl(phenyl)amino]phenyl}ethan-1-ol (1.0 g, 4.4 mmol) was stirred in 4N HCl/dioxane (8 mL) at 0° C. Aminoacetaldehyde diethyl acetal (880 mg, 6.6 mmol) was added, and the reaction stirred for at r.t. for 1 h and then at 108° C. in the microwave for 1 h. The solution was concentrated and purified by silica gel chromatography (0% to 20% MeOH/DCM) to give 150 mg (13%) of the title compound as a yellow oil. [M+H] Calc'd for C₁₇H₂₀N₂O, 269; Found, 269.

Example 146: 3-[({6-[methyl(phenyl)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}methyl)amino]pyridine-4-carboxylic Acid

3-Flouroisonicotinic acid (79 mg, 0.56 mmol), Preparation 146b (150 mg, 0.56 mmol), and DIEA (0.098 mL, 0.56 mmol) were combined in DMA (4 mL) and heated at 168° C. in the microwave for 1 h. The solution was concentrated, and the residue was purified by prep-HPLC to give 18 mg (8%) of the title compound as a tan solid. ¹H NMR (400 MHz, DMSO-d₆): δ 2.60-2.83 (1H, m), 2.79-2.86 (1H, m), 3.23 (3H, s), 3.53-3.59 (1H, m), 3.70-3.82 (2H, m), 4.04-4.10 (1H, m), 4.90-4.96 (1H, m), 6.78-6.98 (5H, m), 7.22-7.28 (3H, m), 7.53 (1H, d, J=4.8 Hz), 7.74 (1H, br s), 7.81 (1H, d, J=4.8 Hz), 8.36 (1H, s), 13.25 (1H, br s). [M+H] Calc'd for C₂₃H₂₃N₃O₃, 390; Found, 390.

Preparation 147a: N-{2-[(tert-butyldimethylsilyl)oxy]ethyl}aniline

To a solution of 2-(phenylamino)ethan-1-ol (2.0 g, 14.6 mmol) and imidazole (2.9 g, 43.7 mmol) in DCM (20 mL) was added TBSCl (2.6 g, 16.0 mmol) at r.t., and the reaction was stirred for 2 h. The reaction was diluted with water (50 mL) and extracted with DCM (50 mL×3). Organics were washed with brine (50 mL), dried (Na₂SO₄), and concentrated. Purification by silica gel chromatography (PE:EtOAc=40:1) gave 3.0 g (82%) of the title compound as a yellow oil.

Preparation 147b: methyl 3-({[(1R)-6-({2-[(tert-butyldimethylsilyl)oxy]ethyl}(phenyl)amino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 122a and N-{2-[(tert-butyldimethylsilyl)oxy]ethyl}aniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₃₂H₄₃N₃O₃Si, 546; Found, 546.

Example 147: 3-({[(1R)-6-[(2-hydroxyethyl)(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

To a solution of Preparation 147b (80 mg, 0.15 mmol) in THF (5 mL) was added TBAF (0.29 mL, 1.0 M in THF, 0.29 mmol) at r.t., and the reaction was stirred for 1 h. To the reaction mixture was added H₂O (5 mL) and LiOH.H₂O (13 mg, 0.30 mmol). The reaction was stirred at r.t. for 2 h. The solution was concentrated to remove THF, and the residue was acidified to pH=5 with 1.0 N aqueous HCl solution. The solid was collected by filtration and then purified by prep-HPLC to give compound 30 mg (48%) of the title compound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 1.65-1.68 (1H, m), 1.74-1.84 (3H, m), 2.62-2.67 (2H, m), 3.04-3.07 (1H, m), 3.41-3.46 (1H, m), 3.54-3.60 (3H, m), 3.72 (2H, d, J=4.8 Hz), 4.73 (1H, br s), 6.80-6.93 (3H, m), 6.92 (2H, d, J=5.7 Hz), 7.19-7.24 (3H, m), 7.55 (1H, d, J=3.9 Hz), 7.83 (1H, d, J=3.6 Hz), 8.36 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Preparation 148a: tert-butyl N-{[(4R)-7-[methyl(6-methylpyridin-2-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 27% yield from Preparation 18d and N,6-dimethylpyridin-2-amine according to the general procedure outlined for Preparation 6e. [M+H] Calc'd for C₂₂H₂₉N₃O₃, 384; Found, 384.

Preparation 148b: N-[(4R)-4-(aminomethyl)-3,4-dihydro-2H-1-benzopyran-7-yl]-N,6-dimethylpyridin-2-amine

The title compound was prepared in quantitative yield from Preparation 148a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₇H₂₁N₃O, 284; Found, 284.

Preparation 148c: methyl 3-({[(4R)-7-[methyl(6-methylpyridin-2-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 77% yield from Preparation 148b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₆N₄O₃, 419; Found, 419.

Example 148: 3-({[(4R)-7-[methyl(6-methylpyridin-2-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 78% yield from Preparation 148c according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.88-2.01 (2H, m), 2.32 (3H, s), 3.09-3.16 (1H, m), 3.32 (3H, s), 3.46-3.54 (1H, m), 3.67-3.73 (1H, m), 4.13-4.21 (2H, m), 6.31 (1H, d, J=8.4 Hz), 6.50 (1H, d, J=7.2 Hz), 6.64 (1H, d, J=2.4 Hz), 6.72-6.75 (1H, m), 7.25-7.33 (2H, m), 7.55 (1H, d, J=5.1 Hz), 7.83 (1H, d, J=4.8 Hz), 8.39 (1H, s). [M+H] Calc'd for C₂₃H₂₄N₄O₃, 405; Found, 405.

Preparation 149a: tert-butyl 1-(aminomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

Methanesulfonyl chloride (0.324 mL, 4.18 mmol) was added to a solution of tert-butyl 1-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (1.0 g, 3.8 mmol) and DIEA (0.812 mL, 4.56 mmol) in DCM (20 mL) at r.t., and the solution was stirred overnight. The solution was washed with brine, dried (MgSO₄), and concentrated to give the crude mesylate intermediate.

This mesylate intermediate was stirred in DMF (8 mL) with sodium azide (1.5 g, 22.8 mmol) at 52° C. overnight. The reaction was diluted with EtOAc (30 mL), filtered, and concentrated. The residue was dissolved in MeOH (30 mL) and hydrogenated under a balloon of H₂ in the presence of 10% Pd/C overnight. The reaction was filtered through Celite and concentrated. Purification by silica gel chromatography (0% to 20% MeOH/DCM) gave 250 mg (25%) of the title compound as a clear oil. [M+H] Calc'd for C₁₅H₂₂N₂O₂, 263; Found, 263.

Example 149: 3-[(1,2,3,4-tetrahydroisoquinolin-1-ylmethyl)amino]pyridine-4-carboxylic Acid

3-Flouroisonicotinic acid (135 mg, 0.95 mmol), Preparation 149a (250 mg, 0.95 mmol), and DIEA (0.17 mL, 0.95 mmol) were combined in DMA (4 mL) and heated at 168° C. in the microwave for 1 h. The solution was concentrated, and then the residue stirred in 50% TFA/DCM (4 mL) for 1 h. The solution was concentrated, and the residue was purified by prep-HPLC to give 28 mg (7%) of the title compound as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 3.00-3.05 (2H, m), 3.28-3.33 (1H, m), 3.54-3.60 (1H, m), 3.80-3.86 (1H, m), 4.05-4.09 (1H, m), 4.87 (1H, br s), 7.26-7.35 (3H, m), 7.50 (1H, d, J=6.2 Hz), 7.71 (1H, d, J=5.0 Hz), 7.80-7.85 (1H, m), 7.99 (1H, d, J=4.8 Hz), 8.55 (1H, s), 8.90 (1H, br s), 9.40 (1H, br s). [M+H] Calc'd for C₁₆H₁₇N₃O₂, 284; Found, 284.

Preparation 150a: methyl 3-({[(1R)-6-[(3-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 43% yield from Preparation 122a and 3-fluoro-N,4-dimethylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Example 150: 3-({[(1R)-6-[(3-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 92% yield from Preparation 150a according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.64-1.67 (1H, m), 1.76-1.83 (3H, m), 2.65-2.67 (2H, m), 3.01-3.06 (1H, m), 3.19 (3H, s), 3.41-3.44 (1H, m), 3.53-3.59 (1H, m), 3.67 (3H, s), 6.40-6.45 (3H, m), 6.80-6.84 (2H, m), 7.09 (1H, t, J=8.1 Hz), 7.24 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=4.5 Hz), 7.80 (1H, d, J=3.9 Hz), 8.32 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Preparation 151a: 3-fluoro-N,4-dimethylaniline

To a suspension of 4-bromo-2-fluoro-1-methylbenzene (1.0 g, 5.3 mmol), KOAc (1.3 g, 13.2 mmol), and CuI (1.2 g, 6.4 mmol) in DMF (20 mL) was added methylamine (26.5 mL, 2.0M in THF, 53.0 mmol) at r.t. under N₂. The reaction was stirred at 100° C. overnight in a sealed tube. The reaction mixture was filtered, diluted with water (50 mL), and extracted with EtOAc (50 mL×3). The organic layers were washed with ammonium hydroxide (50 mL×3) and brine (50 mL), dried (Na₂SO₄), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=20:1) to give 310 mg (42%) of the title compound as a yellow oil. [M+H] Calc'd for C₈H₁₀FN, 140; Found, 140.

Preparation 151b: methyl 3-({[(4R)-7-[(3-fluoro-4-methylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 58% yield from Preparation 126b and 3-fluoro-N,4-dimethylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₅H₂₆FN₃O₃, 436; Found, 436.

Example 151: 3-({[(4R)-7-[(3-fluoro-4-methylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 93% yield from Preparation 151b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.83-1.89 (1H, m), 1.93-1.98 (1H, m), 2.12 (3H, s), 3.04-3.08 (1H, m), 3.16 (3H, s), 3.42-3.49 (1H, m), 3.63-3.69 (1H, m), 4.09-4.18 (2H, m), 6.41 (1H, d, J=2.4 Hz), 6.53 (1H, dd, J=2.4, 8.4 Hz), 6.62-6.70 (2H, m), 7.06-7.12 (1H, m), 7.21 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=5.1 Hz), 7.81 (1H, d, J=5.1 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₄H₂₄FN₃O₃, 422; Found, 422.

Preparation 152a: tert-butyl N-{[(4R)-7-(methylamino)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

To a suspension of Preparation 18d (1.00 g, 2.91 mmol), KOAc (710 mg, 7.25 mmol), methylamine (15 mL, 2 M in THF) in DMF (30 mL) was added CuI (663 mg, 3.49 mmol) at r.t. under N₂. The reaction was sealed and stirred at 100° C. overnight. The reaction was diluted with EtOAc, filtered, and washed with sat NaHCO₃ (10 mL). The organic layer was concentrated, and the residue was purified by silica gel chromatography (PE:EtOAc=5:1) to give 286 mg (34%) of the title compound as a yellow solid. [M+H] Calc'd for C₁₆H₂₄N₂O₃, 293; Found, 293.

Preparation 152b: tert-butyl N-{[(4R)-7-[(5-chloropyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

To a suspension of Preparation 152a (116 mg, 0.40 mmol), 5-bromo-2-chloropyridine (153 mg, 0.80 mmol), S-phos (24 mg, 0.06 mmol) and Cs₂CO₃ (182 mg, 0.56 mmol) in toluene (20 mL) was added Pd₂dba₃ (36 mg, 0.04 mmol) at r.t. under N₂. The reaction was stirred at 120° C. overnight. The reaction was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=5:1) to give 63 mg (39%) of the title compound as a yellow solid. [M+H] Calc'd for C₂₁H₂₆ClN₃O₃, 404; Found, 404.

Preparation 152c: N-[(4R)-4-(aminomethyl)-3,4-dihydro-2H-1-benzopyran-7-yl]-5-chloro-N-methylpyridin-2-amine

The title compound was prepared in 97% yield from Preparation 152b according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₆H₁₈ClN₃O, 304; Found, 304.

Preparation 152d: methyl 3-({[(4R)-7-[(5-chloropyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 47% yield from Preparation 152c according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₃H₂₃ClN₄O₃, 439; Found, 439.

Example 152: 3-({[(4R)-7-[(5-chloropyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 70% yield from Preparation 152d according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.88-2.21 (2H, m), 3.15-3.25 (1H, m), 3.33 (3H, s), 3.49-3.56 (1H, m), 3.71-3.74 (1H, m), 4.20-4.24 (2H, m), 6.52 (1H, d, J=9.3 Hz), 6.71 (1H, s), 6.78 (1H, dd, J=7.8 Hz), 7.38 (1H, d, J=6.6 Hz), 7.50 (1H, d, J=9.3 Hz), 7.58 (1H, d, J=3.0 Hz), 7.85 (1H, dd, J=4.5, 1.5 Hz), 8.15 (1H, s), 8.41 (1H, s). [M+H] Calc'd for C₂₂H₂₁ClN₄O₃, 425; Found, 425.

Preparation 153a: 2-chloro-5-cyclopropylpyridine

To a suspension of 5-bromo-2-chloropyridine (990 mg, 5.15 mmol), cyclopropylboronic acid (893 mg, 10.39 mmol) and Cs₂CO₃ (5.082 g, 15.45 mmol) in 1,4-dioxane (25 mL) was added Pd(PPh₃)₄ (601 mg, 0.52 mmol) at r.t. under N₂. The reaction was stirred at 100° C. for 1 h. After filtration, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography (PE:EtOAc=50:1) to give 452 mg (57%) of the title compound as a colorless oil. [M+H] Calc'd for C₈H₈NCl, 154; Found, 154.

Preparation 153b: tert-butyl N-{[(4R)-7-[(5-cyclopropylpyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

To a suspension of 2-chloro-5-cyclopropylpyridine (333 mg, 2.18 mmol), Preparation 152a (317 mg, 1.09 mmol), S-phos (70 mg, 0.17 mmol) and Cs₂CO₃ (499 mg, 1.53 mmol) in toluene (20 mL) was added Pd₂dba₃ (101 mg, 0.11 mmol) at r.t. under N₂. The reaction was stirred at 120° C. overnight. After filtration, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography (PE:EtOAc=10:1) to give 330 mg (75%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₄H₃₁N₃O₃, 410; Found, 410.

Preparation 153c: N-[(4R)-4-(aminomethyl)-3,4-dihydro-2H-1-benzopyran-7-yl]-5-cyclopropyl-N-methylpyridin-2-amine

The title compound was prepared in 94% yield from Preparation 153b according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₉H₂₃N₃O, 310; Found, 310.

Preparation 153d: methyl 3-({[(4R)-7-[(5-cyclopropylpyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 86% yield from Preparation 153d according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₆H₂₈N₄O₃, 445; Found, 445.

Example 153: 3-({[(4R)-7-[(5-cyclopropylpyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 39% yield from Preparation 153d according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 0.55-0.59 (2H, m), 0.83-0.89 (2H, m), 1.78-2.02 (3H, m), 3.12-3.15 (1H, m), 3.31 (3H, s), 3.48-3.55 (1H, m), 3.72 (1H, dd, J=4.2, 13.5 Hz), 4.14-4.22 (2H, m), 6.53 (1H, d, J=8.4 Hz), 6.63 (1H, s), 6.74-6.71 (1H, m), 7.12 (1H, dd, J=2.1, 8.4 Hz), 7.31 (1H, d, J=8.4 Hz), 7.57 (1H, d, J=4.8 Hz), 7.85 (1H, d, J=5.1 Hz), 8.00 (1H, s), 8.41 (1H, s). [M+H] Calc'd for C₂₅H₂₆N₄O₃, 431; Found, 431.

Preparation 154a: 4-ethyl-N-methylaniline

The title compound was prepared in 60% overall yield from 4-ethylaniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₉H₁₃N, 136; Found, 136.

Preparation 154b: methyl 3-({[(4R)-7-[(4-ethylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 48% yield from Preparation 126b and 4-ethyl-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Example 154: 3-({[(4R)-7-[(4-ethylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 82% yield from Preparation 154b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.15 (3H, t, J=7.5 Hz), 1.80-1.85 (1H, m), 1.90-1.97 (1H, m), 2.54 (2H, q, J=7.5 Hz), 3.00-3.04 (1H, m), 3.15 (3H, s), 3.40-3.47 (1H, m), 3.62 (1H, dd, J=5.1, 13.5 Hz), 4.06-4.14 (2H, m), 6.23 (1H, d, J=2.1 Hz), 6.38 (1H, dd, J=8.1, 2.4 Hz), 6.95 (2H, d, J=8.1 Hz), 7.12 (3H, dd, J=3.6, 8.1 Hz), 7.55 (1H, d, J=4.8 Hz), 7.82 (1H, d, J=4.8 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Preparation 155a: tert-butyl N-{[(1R)-6-[methyl(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a suspension of Preparation 139a (200 mg, 0.69 mmol), 4-bromo-1-methyl-1,2-dihydropyridin-2-one (259 mg, 1.38 mmol), S-phos (45 mg, 0.11 mmol) and Cs₂CO₃ (315 mg, 0.97 mmol) in toluene (20 mL) was added Pd₂dba₃ (64 mg, 0.07 mmol) at r.t. under N₂. The reaction was stirred at 120° C. overnight. The reaction was cooled, filtered, and concentrated. The residue was purified by silica gel chromatography (DCM:MeOH=15:1) to give 162 mg (59%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₃H₃₁N₃O₃, 398; Found, 398.

Preparation 155b: 4-{[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl](methyl)amino}-1-methyl-1,2-dihydropyridin-2-one

The title compound was prepared in 54% yield from Preparation 155a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₈H₂₃N₃O, 298; Found, 298.

Preparation 155c: methyl 3-({[(1R)-6-[methyl(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 65% yield from Preparation 155b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₅H₂₈N₄O₃, 433; Found, 433.

Example 155: 3-({[(1R)-6-[methyl(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 42% yield from Preparation 155c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.76-1.87 (4H, m), 2.67-2.78 (2H, m), 3.28 (3H, s), 3.41 (3H, s), 3.42-3.51 (2H, m), 3.60-3.65 (1H, m), 5.45 (1H, s), 5.65-5.67 (1H, m), 6.67 (2H, m), 7.31-7.38 (2H, m), 7.55 (1H, m), 7.82 (1H, s), 8.34 (1H, s). [M+H] Calc'd for C₂₄H₂₆N₄O₃, 418; Found, 419.

Preparation 156a: tert-butyl N-{[(1R)-6-[methyl(5-methylpyrimidin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 21% yield form Preparation 139a and 2-chloro-5-methylpyrimidine according to the general procedure outlined for Preparation 155a. [M+H] Calc'd for C₂₂H₃₀N₄O₂, 383; Found, 383.

Preparation 156b: N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N,5-dimethylpyrimidin-2-amine

The title compound was prepared in 98% yield from Preparation 156a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₇H₂₂N₄, 283; Found, 283.

Preparation 156c: methyl 3-({[(1R)-6-[methyl(5-methylpyrimidin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 59% yield from Preparation 156b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₇N₅O₂, 418; Found, 418.

Example 156: 3-({[(1R)-6-[methyl(5-methylpyrimidin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 57% yield from Preparation 156c according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.68-1.71 (1H, m), 1.83-1.86 (3H, m), 2.09 (3H, s), 2.67-2.73 (2H, m), 3.09-3.12 (1H, m), 3.39 (3H, s), 3.42-3.48 (1H, m), 3.62 (1H, dd, J=4.8, 12.8 Hz), 7.02 (1H, s), 7.06 (1H, d, J=8.4 Hz), 7.32 (1H, d, J=8.4 Hz), 7.58 (1H, d, J=4.8 Hz), 7.84 (1H, d, J=4.8 Hz), 8.21 (2H, s), 8.38 (1H, s). [M+H] Calc'd for C₂₃H₂₅N₅O₂, 403; Found, 404.

Preparation 157a: 5-ethyl-N-methylpyridin-2-amine

A solution of 5-ethylpyridin-2-amine (330 mg, 2.70 mmol) in THF (10 mL) was cooled to −78° C. and n-BuLi (1.2 mL, 3.0 mmol) was added. The reaction stirred at −78° C. for 30 min, and then MeI (423 mg, 2.97 mmol) was added. The reaction was stirred for 2 h while warming to r.t. Water (10 mL) was added, and the solution was extracted with EtOAc (20 mL). The organic layer was dried (Na₂SO₄) and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=5:1) to give 35 mg (9%) of the title compound as a yellow oil. [M+H] Calc'd for C₈H₁₂N₂, 137; Found, 137.

Preparation 157b: methyl 3-({[(4R)-7-[(5-ethylpyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 42% yield from Preparation 126b and 5-ethyl-N-methylpyridin-2-amine according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₅H₂₈N₄O₃, 433; Found, 433.

Example 157: 3-({[(4R)-7-[(5-ethylpyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 80% yield from Preparation 157b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.13 (3H, t, J=7.5 Hz), 1.88-2.03 (2H, m), 2.44-2.50 (2H, m), 3.11-3.13 (1H, m), 3.49 (3H, s), 3.47-3.50 (1H, m), 3.67-3.74 (1H, m), 4.17-4.23 (2H, m), 6.56 (1H, d, J=8.7 Hz), 6.64 (1H, m), 6.72-6.76 (1H, m), 7.33 (2H, d, J=8.1 Hz), 7.58 (1H, d, J=5.1 Hz), 7.83 (1H, d, J=4.8 Hz), 8.01 (1H, d, J=1.8 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₄H₂₆N₄O₃, 419; Found, 419.

Preparation 158a: [4-(methylamino)phenyl]methanol

To a solution of methyl 4-(methylamino)benzoate (2.0 g, 12.1 mmol) in THF (30 mL) was added LAH (6.1 mL, 2.4 M in THF, 14.5 mmol) at 0° C. The reaction was stirred at r.t. for 2 h. The reaction was quenched with EtOAc (50 mL) and water (2 mL). The mixture was dried (Na₂SO₄) and concentrated. Purification by silica gel chromatography (PE:EtOAc=3:1) gave 1.0 g (60%) of the title compound as a yellow oil. [M+H] Calc'd for C₈H₁₁NO, 138; Found 138.

Preparation 158b: 4-{[(tert-butyldimethylsilyl)oxy]methyl}-N-methylaniline

To a solution of [4-(methylamino)phenyl]methanol (500 mg, 3.7 mmol) and imidazole (248 mg, 3.7 mmol) in DCM (20 mL) was added TBSCl (548 mg, 3.7 mmol) at r.t., and the reaction was stirred for 2 h. The reaction was diluted with water (50 mL) and extracted with DCM (50 mL×3). Organics were washed with brine (50 mL), dried (Na₂SO₄), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=40:1) to give 600 mg (66%) of the title compound as a yellow oil. [M+H] Calc'd for C₁₄H₁₅NOSi, 252; Found 252.

Preparation 158c: methyl 3-{[(1R)-6-[(4-{[(tert-butyldimethylsilyl)oxy]methyl}phenyl)-(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 126b and Preparation 158b according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₃₂H₄₃N₃O₃Si, 546; Found, 546.

Example 158: 3-({[(1R)-6-{[4-(hydroxymethyl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

To a solution of Preparation 158c (80 mg, 0.15 mmol) in THF (5 mL) was added TBAF (0.29 mL, 1.0 M in THF, 0.29 mmol) at r.t., and the reaction was stirred for 1 h. Water (5 mL) and LiOH.H₂O (26 mg, 0.60 mmol) were added, and the reaction was stirred at r.t. for 2 h. THF was removed in vacuo, and the residue was acidified to pH=5 with 1.0 N aqueous HCl solution. The precipitate was filtered and purified by prep-HPLC to give 40 mg (65%) of the title compound as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.65-1.68 (1H, m), 1.77-1.84 (3H, m), 2.64-2.67 (2H, m), 3.03-3.06 (1H, m), 3.20 (3H, s), 3.41-3.46 (1H, m), 3.55-3.60 (1H, m), 4.41 (2H, s), 5.01 (1H, br s), 6.72-6.76 (2H, m), 6.92 (2H, d, J=8.4 Hz), 7.19-7.21 (3H, m), 7.56 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=5.2 Hz), 8.35 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Preparation 159a: methyl 3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a suspension of Preparation 122a (300 mg, 0.796 mmol), N,1-dimethyl-1H-pyrazol-4-amine (106 mg, 0.955 mmol), S-phos (49 mg, 0.119 mmol) and Cs₂CO₃ (363 mg, 1.114 mmol) in toluene (30 mL) was added Pd₂dba₃ (73 mg, 0.080 mmol) at r.t. under N₂. The reaction was stirred at 120° C. overnight. The reaction was cooled, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=5:1) to give 100 mg (32%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₃H₂₇N₅O₂, 406; Found, 406.

Example 159: 3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 52% yield from Preparation 159a according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.73-1.76 (4H, m), 2.62 (2H, m), 2.91 (1H, s), 3.09 (3H, s), 3.44-3.50 (2H, m), 3.64-3.69 (1H, m), 3.78 (3H, s), 6.51-6.52 (1H, m), 6.60 (1H, m), 7.07-7.10 (1H, m), 7.29 (1H, s), 7.53-7.54 (1H, d, J=4.8 Hz), 7.60 (1H, s), 7.78-7.80 (1H, m), 8.29 (1H, s). [M+H] Calc'd for C₂₂H₂₅N₅O₂, 392; Found, 392.

Preparation 160a: 1-N,1-N,4-N-trimethylbenzene-1,4-diamine

The title compound was prepared in 52% overall yield from 1-N,1-N-dimethylbenzene-1,4-diamine according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₉H₁₄N₂, 151; Found, 151.

Preparation 160b: methyl 3-({[(1R)-6-{[4-(dimethylamino)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 23% yield from Preparation 122a and Preparation 160a according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₃₂N₄O₂, 445; Found, 445.

Example 160: 3-({[(1R)-6-{[4-(dimethylamino)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 11% yield from Preparation 164b according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.61-1.64 (1H, m), 1.75-1.80 (3H, m), 2.60-2.61 (2H, m), 2.88 (6H, s), 2.97-2.98 (1H, m), 3.12 (3H, s), 3.48-3.52 (2H, m), 6.42-6.49 (2H, m), 6.73 (2H, d, J=6.8 Hz), 6.97 (2H, d, J=6.8 Hz), 7.07 (1H, d, J=8.0 Hz), 7.55 (1H, d, J=4.8 Hz), 7.81 (1H, d, J=4.8 Hz), 8.30 (1H, s). [M+H] Calc'd for C₂₆H₃₀N₄O₂, 431; Found, 431.

Preparation 161a: methyl 3-({[(1R)-6-[(4-cyclopropylphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 122a and 4-cyclopropyl-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₈H₃₁N₃O₂, 442; Found, 442.

Example 161: 3-({[(1R)-6-[(4-cyclopropylphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 93% yield from Preparation 161a according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 0.56-0.60 (2H, m), 0.84-0.90 (2H, m), 1.60-1.63 (1H, m), 1.75-1.86 (4H, m), 2.62-2.64 (2H, m), 2.97-3.01 (1H, m), 3.15 (3H, s), 3.34-3.41 (1H, m), 3.50-3.56 (1H, m), 6.65-6.69 (2H, m), 6.86 (2H, d, J=8.1 Hz), 6.97 (2H, d, J=8.7 Hz), 7.15 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=4.8 Hz), 7.80 (1H, d, J=4.8 Hz), 8.31 (1H, s). [M+H] Calc'd for C₂₇H₂₉N₃O₂, 428; Found, 428.

Preparation 162a: tert-butyl N-{[(1R)-6-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 69% yield from Preparation 6d and 2,3,4,5-tetrahydro-1H-1-benzazepine according to the general procedure outlined for Preparation 9a. [M+H] Calc'd for C₂₆H₃₄N₂O₂, 407; Found, 407.

Preparation 162b: [(1R)-6-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in quantitative yield from Preparation 162a according to the procedure for Preparation 43b. [M+H] Calc'd for C₂₁H₂₆N₂, 307; Found, 307.

Preparation 162c: methyl 3-({[(1R)-6-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 76% yield from Preparation 162b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₈H₃₁N₃O₂, 442; Found, 442.

Example 162: 3-({[(1R)-6-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 65% yield from Preparation 145c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.56-1.89 (8H, m), 2.58 (4H, br s), 2.93-2.99 (1H, m), 3.32-3.39 (1H, m), 3.47-3.60 (3H, m), 6.28 (1H, s), 6.33-6.37 (1H, m), 7.04-7.11 (2H, m), 7.14-7.26 (2H, m), 7.30-7.36 (1H, m), 7.56 (d, 1H, J=5.0 Hz), 7.82 (1H, d, J=5.0 Hz), 8.36 (1H, s). [M+H] Calc'd for C₂₇H₂₉N₃O₂, 428; Found, 428.

Preparation 163a: 4-cyclopropyl-N-(2-methoxyethyl)aniline

Methoxyacetyl chloride (0.55 mL, 6.0 mmol) was added to a solution of 4-cyclopropylaniline (800 mg, 6.0 mmol) and DIEA (1.05 mL, 6.0 mmol) in DCM, and the reaction was stirred at r.t. for 2 h. The reaction was washed with brine, dried (MgSO₄), and concentrated to give crude N-(4-cyclopropylphenyl)-2-methoxyacetamide.

To a solution of this N-(4-cyclopropylphenyl)-2-methoxyacetamide in THF (20 mL) was added LAH (5.0 mL, 2.4 M in THF, 12 mmol) at 0° C. The reaction was stirred at r.t. for 2 h. The solution was diluted with water (0.5 mL) and EtOAc (30 mL), dried (Na₂SO₄), and concentrated. Purification by silica gel chromatography (0% to 15% MeOH/DCM) gave 912 mg (79%) of the title compound as a yellow oil. [M+H] Calc'd for C₁₂H₁₇NO, 192; Found, 192.

Preparation 163b: tert-butyl N-{[(1R)-6-[(4-cyclopropylphenyl)(2-methoxyethyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 69% yield from Preparation 6d and 4-cyclopropyl-N-(2-methoxyethyl)aniline according to the general procedure outlined for Preparation 9a. [M+H] Calc'd for C₂₈H₃₈N₂O₃, 451; Found, 451.

Preparation 163c: (5R)-5-(aminomethyl)-N-(4-cyclopropylphenyl)-N-(2-methoxyethyl)-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation 163b according to the procedure for Preparation 43b. [M+H] Calc'd for C₂₃H₃₀N₂O, 351; Found, 351.

Preparation 163d: methyl 3-({[(1R)-6-[(4-cyclopropylphenyl)(2-methoxyethyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 72% yield from Preparation 163c according to the procedure for Preparation 4d. [M+H] Calc'd for C₃₀H₃₅N₃O₃, 486; Found, 486.

Example 163: 3-({[(1R)-6-[(4-cyclopropylphenyl)(2-methoxyethyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 65% yield from Preparation 163d according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 0.58-0.62 (2H, m), 0.85-0.91 (2H, m), 1.61-1.67 (1H, m), 1.71-1.85 (4H, m), 2.60-2.65 (2H, m), 2.99-3.03 (1H, m), 3.23 (3H, s), 3.37-3.57 (4H, m), 3.75-3.80 (2H, m), 6.65 (1H, s), 6.68 (1H, d, J=8.6 Hz), 6.89 (2H, d, J=7.0 Hz), 6.97 (2H, d, J=7.8 Hz), 7.16 (1H, d, J=8.2 Hz), 7.55 (1H, d, J=4.5 Hz), 7.81 (1H, d, J=4.5 Hz), 8.32 (1H, s). [M+H] Calc'd for C₂₉H₃₃N₃O₃, 472; Found, 472.

Preparation 164a: 4-(methoxymethyl)-N-methylaniline

The title compound was prepared in 22% overall yield from 4-methoxymethylaniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₉H₁₃NO, 152; Found, 152.

Preparation 164b: methyl 3-({[(1R)-6-{[4-(methoxymethyl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 23% yield from Preparation 122a and 4-(methoxymethyl)-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₃₁N₃O₃, 446; Found, 446.

Example 164: 3-({[(1R)-6-{[4-(methoxymethyl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 33% yield from Preparation 164b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.59-1.79 (4H, m), 2.61-2.67 (2H, m), 3.02-3.04 (1H, m), 3.20 (3H, s), 3.23 (3H, s), 3.31-3.40 (1H, m), 3.51-3.54 (1H, m), 4.28 (2H, s), 6.77-6.88 (4H, m), 7.14-7.24 (3H, m), 7.54 (1H, d, J=4.2 Hz), 7.80 (1H, d, J=4.8 Hz), 8.31 (1H, s). [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Preparation 165a: 4-((tert-butyldimethylsilyl)oxy)-N-methylaniline

A solution of 4-(methylamino)phenol (5.0 g, 29 mmol), TBDMSCl (4.8 g, 32 mmol) and imidazole (9.9 g, 0.15 mol) in DCM was stirred at r.t. for 1 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was dried (Na₂SO₄), concentrated and purified by silica gel chromatography (PE:EtOAc=10:1) to give 3.0 g (43%) of the title compound as a dark green oil. [M+H] Calc'd for C₁₃H₂₃NOSi, 238; Found, 238.

Preparation 165b: methyl 3-({[(1R)-6-({4-[(tert-butyldimethylsilyl)oxy]phenyl}-(methyl)amino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 36% yield from Preparation 122a and 4-((tert-butyldimethylsilyl)oxy)-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₃₁H₄₁N₃O₃Si, 532; Found, 532.

Preparation 165c: methyl 3-({[(1R)-6-[(4-hydroxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 165b (733 mg, 1.37 mmol) in THF (10 mL) was added TBAF (3 mL, 3 mmol, 1 M) slowly. The mixture was stirred at r.t. for 20 min. EtOAc (10 mL) and then water (10 mL) was added to the solution. The organic layer was separated, dried over Na₂SO₄, concentrated, and purified by silica gel chromatography (PE:EtOAc=2:1) to give 576 mg (100%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Example 165: 3-({[(1R)-6-[(4-hydroxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 88% yield from Preparation 165c according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.59-1.81 (4H, m), 2.48-2.58 (2H, m), 2.92-3.00 (1H, m), 3.10 (3H, s), 3.27-3.51 (2H, m), 6.41 (1H, s), 6.46 (1H, dd, J=8.7, 1.5 Hz), 7.33 (2H, d, J=8.7 Hz), 6.91 (2H, d, J=8.7 Hz), 7.06 (1H, d, J=8.1 Hz), 7.53 (1H, d, J=4.8 Hz), 7.78 (1H, d, J=4.8 Hz), 8.27 (1H, s), 9.26 (1H, br s). [M+H] Calc'd for C₂₄H₂₅N₃O₃, 404; Found, 404.

Preparation 166a: N,3,5-trimethyl-1,2-oxazol-4-amine

The title compound was prepared in 33% overall yield from dimethyl-1,2-oxazol-4-amine according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₆H₁₀N₂O, 127; Found, 127.

Preparation 166b: methyl 3-({[(1R)-6-[(dimethyl-1,2-oxazol-4-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 36% yield from Preparation 122a and N,3,5-trimethyl-1,2-oxazol-4-amine according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₄H₂₈N₄O₃, 421; Found, 421.

Example 166: 3-({[(1R)-6-[(dimethyl-1,2-oxazol-4-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 91% yield from Preparation 166b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.61-1.64 (1H, m), 1.73-1.82 (3H, m), 1.95 (3H, s), 2.19 (3H, s), 2.62-2.66 (2H, m), 2.96-3.00 (1H, m), 3.09 (3H, s), 3.38-3.41 (1H, m), 3.47-3.53 (1H, m), 6.31-6.33 (2H, m), 7.10 (1H, d, J=8.4 Hz), 7.53 (1H, d, J=5.1 Hz), 7.80 (1H, d, J=5.1 Hz), 8.31 (1H, s). [M+H] Calc'd for C₂₃H₂₆N₄O₃, 407; Found, 407.

Preparation 167a: N-methyl-4-(pyrrolidin-1-yl)aniline

The title compound was prepared in 74% overall yield from 4-(pyrrolidin-1-yl)aniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₁₁H₁₆N₂, 177; Found, 177.

Preparation 167b: methyl 3-({[(1R)-6-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 55% yield from Preparation 122a and N-methyl-4-(pyrrolidin-1-yl)aniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₉H₃₄N₄O₂, 471; Found, 471.

Example 167: 3-({[(1R)-6-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 77% yield from Preparation 167b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.58-1.62 (1H, m) 1.69-1.78 (3H, m), 1.89-1.94 (4H, m), 2.55-2.58 (2H, m), 2.92-2.96 (1H, m), 3.09 (3H, s), 3.30-3.33 (4H, m), 3.37-3.43 (1H, m), 3.46-3.49 (1H, m), 6.36 (1H, s), 6.42 (1H, d, J=9.0 Hz), 6.52 (2H, d, J=8.7 Hz), 6.94 (2H, d, J=8.4 Hz), 7.03 (1H, d, J=9.0 Hz), 7.53 (1H, d, J=4.8 Hz), 7.79 (1H, d, J=4.5 Hz), 8.29 (1H, s). [M+H] Calc'd for C₂₈H₃₂N₄O₂, 457; Found, 457.

Preparation 168a: [1-(4-bromophenyl)ethoxy](tert-butyl)dimethylsilane

To a solution of 1-(4-bromophenyl)ethan-1-ol (2.8 g, 13.93 mmol) and imidazole (2.84 g, 41.79 mmol) in DMF (35 mL) was added TBDMSCl (4.18 g, 27.86 mmol) at r.t., and the reaction was stirred overnight. The reaction was diluted with water (70 mL) and extracted with EtOAc (50 mL×3). Organics were washed with brine (50 mL), dried (Na₂SO₄), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=100:1) to give 4.08 g (95%) of the title compound as a colorless oil.

Preparation 168b: 4-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-N-methylaniline

To a suspension of Preparation 168a (1.0 g, 3.18 mmol), KOAc (780 mg, 7.96 mmol), and methylamine (16 mL, 2 M in THF) in DMF (30 mL) was added CuI (728 mg, 3.83 mmol) at r.t. under N₂. The reaction vessel was sealed and stirred at 100° C. overnight. After filtration, the solution was diluted with ammonium hydroxide (10 mL) and extracted with EtOAc. The organic layer was concentrated in vacuo, and the residue was purified by silica gel chromatography (PE:EtOAc=5:1) to give 490 mg (58%) of the title compound as a colorless oil. [M+H] Calc'd for C₁₅H₂₇NOSi, 266; Found, 266.

Preparation 168c: methyl 3-[({6-[(4-{1-[(tert-butyldimethylsilyl)oxy]ethyl}phenyl)-(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)amino]pyridine-4-carboxylate

The title compound was prepared in 32% yield from Preparation 122a and Preparation 168b according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₃₃H₄₅N₃O₃Si, 560; Found, 560.

Preparation 168d: methyl 3-({[6-({4-[(1R)-1-hydroxyethyl]phenyl}(methyl)amino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 169d: methyl 3-({[6-({4-[(1S)-1-hydroxyethyl]phenyl}(methyl)amino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 168c (333 mg, 0.60 mmol) in THF (5 mL) was added TBAF (1.2 mL, 1.0 M in THF, 1.2 mmol) at r.t., and the reaction was stirred for 1 h. The solution was diluted with EtOAc (30 mL) and water (10 mL), and acidified to pH=5 with 5N HCl. This mixture was extracted with EtOAc (50 mL×3), washed with brine (50 mL), dried (Na₂SO₄), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=1:1) to give 142 mg (54%) of the racemate as a yellow solid. [M+H] Calc'd for C₂₇H₃₁N₃O₃, 446; Found, 446.

Separation by chiral prep-HPLC (Column: Chiralcel IA 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=80:20; F: 1.0 mL/min; W: 230 nm; T: 30° C.) gave 50 mg (30%) of Preparation 168d (8.622 min) and 55 mg (33%) of Preparation 169d (9.751 min), each as a yellow solid. Assignment of the hydroxyethyl stereocenter is arbitrary.

Example 168: 3-({[6-({4-[(1R)-1-hydroxyethyl]phenyl}(methyl)amino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 15% yield from Preparation 168d according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.30 (3H, d, J=6.4 Hz), 1.63-1.67 (1H, m), 1.77-1.84 (3H, m), 2.64-2.67 (2H, m), 3.03-3.05 (1H, m), 3.20 (3H, s), 3.39-3.41 (1H, m), 3.42-3.44 (1H, m), 3.54-3.58 (1H, m), 4.64-4.66 (1H, m), 5.01 (1H, s), 6.71-6.75 (2H, m), 6.92 (2H, d, J=8.0 Hz), 7.19-7.24 (3H, m), 7.56 (1H, d, J=5.2 Hz), 7.82 (1H, d, J=4.8 Hz), 8.33 (1H, s). [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Example 169: 3-({[6-({4-[(1S)-1-hydroxyethyl]phenyl}(methyl)amino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 17% yield from Preparation 169d according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.30 (3H, d, J=6.4 Hz), 1.63-1.67 (1H, m), 1.75-1.82 (3H, m), 2.64-2.67 (2H, m), 2.99-3.04 (1H, m), 3.20 (3H, s), 3.34-3.38 (2H, m), 3.50-3.55 (1H, m), 4.63-4.67 (1H, m), 5.01 (1H, s), 6.71-6.75 (2H, m), 6.92 (2H, d, J=8.4 Hz), 7.20-7.23 (3H, m), 7.57 (1H, d, J=5.2 Hz), 7.78 (1H, d, J=4.8 Hz), 8.24 (1H, s). [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Preparation 170a: N-methyl-4-(morpholin-4-yl)aniline

The title compound was prepared in 48% overall yield from 4-(morpholin-4-yl)aniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₁₁H₁₆N₂O, 193; Found, 193.

Preparation 170b: methyl 3-({[(1R)-6-{methyl[4-(morpholin-4-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 46% yield from Preparation 122a and N-methyl-4-(morpholin-4-yl)aniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₉H₃₄N₄O₃, 487; Found, 487.

Example 170: 3-({[(1R)-6-{methyl[4-(morpholin-4-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 66% yield from Preparation 166b according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.62-1.63 (1H, m), 1.79-1.80 (3H, m), 2.60-2.63 (2H, m) 2.97-2.99 (1H, m), 3.05-3.07 (4H, m), 3.14 (3H, s), 3.31-3.36 (1H, m), 3.48-3.52 (1H, m), 3.72-3.74 (4H, m), 6.51 (1H, m), 6.55-6.57 (1H, m), 6.91-6.99 (4H, m), 7.11 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=4.8 Hz), 7.79 (1H, d, J=4.8 Hz), 8.26 (1H, s). [M+H] Calc'd for C₂₈H₃₂N₄O₃, 473; Found, 473.

Preparation 171a: tert-butyl N-{[(1R)-6-[methyl(5-methyl-1,2-oxazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 55% yield from Preparation 6d and N,5-dimethyl-1,2-oxazol-3-amine according to the general procedure outlined for Preparation 9a. [M+H] Calc'd for C₂₁H₂₉N₃O₃, 372; Found, 372.

Preparation 171b: N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N,5-dimethyl-1,2-oxazol-3-amine

The title compound was prepared in quantitative yield from Preparation 171a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₆H₂₁N₃O, 272; Found, 272.

Preparation 171c: methyl 3-({[(1R)-6-[methyl(5-methyl-1,2-oxazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 69% yield from Preparation 171b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₃H₂₆N₄O₃, 407; Found, 407.

Example 171: 3-({[(1R)-6-[methyl(5-methyl-1,2-oxazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 72% yield from Preparation 171c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.67-1.86 (4H, m), 2.26 (3H, s), 2.63-2.71 (2H, m), 3.02-3.11 (1H, m), 3.24 (3H, s), 3.33-3.65 (2H, m), 5.80 (1H, s), 6.98-7.04 (2H, m), 7.31 (1H, d, J=6.1 Hz), 7.66 (1H, d, J=4.4 Hz), 7.87 (1H, d, J=4.4 Hz), 8.39 (1H, s). [M+H] Calc'd for C₂₂H₂₄N₄O₃, 393; Found, 393.

Preparation 172a: tert-butyl N-{[(1R)-6-[(2-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 39% yield from Preparation 6d and 2-methoxy-N-methylaniline according to the general procedure outlined for Preparation 9a. [M+H] Calc'd for C₂₄H₃₂N₂O₃, 397; Found, 397.

Preparation 172b: (5R)-5-(aminomethyl)-N-(2-methoxyphenyl)-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation 172a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₉H₂₄N₂O, 297; Found, 297.

Preparation 172c: methyl 3-({[(1R)-6-[(2-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 44% yield from Preparation 172b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Example 172: 3-({[(1R)-6-[(2-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 47% yield from Preparation 172c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.55-1.65 (1H, m), 1.71-1.82 (3H, m), 2.57-2.62 (2H, m), 2.87-2.91 (1H, m), 3.10 (3H, s), 3.25-3.35 (2H, m), 3.73 (3H, s), 6.26-6.31 (2H, m), 6.95-7.15 (4H, m), 7.22-7.29 (1H, m), 7.52 (1H, d, J=4.4 Hz), 7.65 (1H, d, J=4.4 Hz), 7.96 (s, 1H). [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Preparation 173a: tert-butyl N-{[(1R)-6-[methyl(pyridin-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 59% yield from Preparation 6d and 4-methylaminopyridine according to the general procedure outlined for Preparation 9a. [M+H] Calc'd for C₂₂H₂₉N₃O₂, 368; Found, 368.

Preparation 173b: N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-methylpyridin-4-amine

The title compound was prepared in quantitative yield from Preparation 173a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₇H₂₁N₃, 268; Found, 268.

Preparation 173c: methyl 3-({[(1R)-6-[methyl(pyridin-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 42% yield from Preparation 173b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₄H₂₆N₄O₂, 403; Found, 403.

Example 173: 3-({[(1R)-6-[methyl(pyridin-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 23% yield from Preparation 173c according to the procedure for Example 1. ¹H NMR (400 MHz, MeOD): δ 1.75-1.84 (1H, m), 1.96-2.05 (3H, m), 2.78-2.95 (2H, m), 3.27-3.32 (1H, m), 3.49 (3H, s), 3.55-3.60 (2H, m), 6.84-6.87 (2H, m), 7.04 (1H, d, J=8.1 Hz), 7.08 (1H, s), 7.47 (1H, d, J=8.1 Hz), 7.78 (2H, br s), 8.09-8.13 (3H, m). [M+H] Calc'd for C₂₃H₂₄N₄O₂, 389; Found, 389.

Preparation 174a: 4-(3,6-dihydro-2H-pyran-4-yl)-N-methylaniline

To a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (800 mg, 3.8 mmol), S-Phos (160 mg, 0.38 mmol), Pd₂(dba)₃ (72 mg, 0.08 mmol), and K₃PO₄ (96 mg, 3.8 mmol) in toluene/H₂O (100 mL/20 mL) was added 4-bromo-N-methylaniline (712 mg, 3.84 mmol) under N₂. After stirring at 115° C. overnight, the reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=10:1) to give 550 mg (76%) of the title compound as a yellow solid. [M+H] Calc'd for C₁₂H₁₅NO, 190; Found, 190.

Preparation 174b methyl 3-({[(1R)-6-{[4-(3,6-dihydro-2H-pyran-4-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 15% yield from Preparation 122a and 4-(3,6-dihydro-2H-pyran-4-yl)-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₃₀H₃₃N₃O₃, 484; Found, 484.

Example 174: 3-({[(1R)-6-{[4-(3,6-dihydro-2H-pyran-4-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 32% yield from Preparation 174b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.62-1.63 (1H, m), 1.75-1.82 (2H, m), 2.38-2.42 (2H, m), 2.67-2.69 (2H, m), 3.05-3.08 (1H, m), 3.20 (3H, s), 3.46-3.49 (2H, m), 3.76-3.84 (4H, m), 4.17-4.18 (2H, m), 6.09 (1H, s), 6.80-6.86 (4H, t, J=9.0 Hz), 7.22-7.24 (1H, d, J=8.1 Hz), 7.28-7.31 (2H, d, J=8.4 Hz), 7.73-7.75 (1H, d, J=5.7 Hz), 7.87-7.89 (1H, d, J=5.1 Hz), 8.39 (1H, s). [M+H] Calc'd for C₂₉H₃₁N₃O₃, 470; Found, 470.

Preparation 175a: N-methyl-4-(oxan-4-yl)aniline

To a solution of compound 4-(3,6-dihydro-2H-pyran-4-yl)-N-methylaniline (200 mg, 1.05 mmol) in EtOAc (20 mL) under N₂ was added 10% Pd/C (50 mg) at r.t. The reaction was stirred overnight under 1 atm H₂. The reaction was filtered through Celite and concentrated to give 180 mg (89%) as a yellow solid. [M+H] Calc'd for C₁₂H₁₅NO, 190; Found, 190.

Preparation 175b: methyl 3-({[(1R)-6-{methyl[4-(oxan-4-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 44% yield from Preparation 122a and N-methyl-4-(oxan-4-yl)aniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₃₀H₃₅N₃O₃, 486; Found, 486.

Example 175: 3-({[(1R)-6-{methyl[4-(oxan-4-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 93% yield from Preparation 175b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.57-1.64 (5H, m) 1.75-1.78 (3H, m), 2.62-2.65 (3H, m), 3.00-3.03 (1H, m), 3.17 (3H, s), 3.35-3.44 (3H, m), 3.51-3.53 (1H, m), 3.89-3.93 (2H, m), 6.70-6.73 (2H, m), 6.88 (2H, d, J=8.4 Hz), 7.11 (2H, d, J=8.4 Hz), 7.18 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=5.1 Hz), 7.1 (1H, d, J=5.1 Hz), 8.33 (1H, s). [M+H] Calc'd for C₂₉H₃₃N₃O₃, 472; Found, 472.

Preparation 176a: 4-ethenyl-N-methylaniline

The title compound was prepared in 13% overall yield from 4-ethenylaniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₉H₁₁N, 134; Found, 134.

Preparation 176b: methyl 3-({[(4R)-7-[(4-ethenylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 38% yield from Preparation 126b and 4-ethenyl-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₆H₂₇N₃O₃, 430; Found, 430.

Example 176: 3-({[(4R)-7-[(4-ethenylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 98% yield from Preparation 176b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.87-1.97 (2H, m), 3.05-3.08 (1H, m), 3.20 (3H, s) 3.42-3.49 (1H, m), 3.63-3.69 (1H, m), 4.11-4.18 (2H, m), 5.06-5.10 (1H, m), 5.60-5.66 (1H, m), 6.42-6.43 (1H, m), 6.53-6.67 (2H, m), 6.90 (2H, d, J=8.4 Hz), 7.21 (1H, d, J=8.1 Hz), 7.33 (2H, d, J=8.7 Hz), 7.55 (1H, d, J=4.8 Hz), 7.82 (1H, d, J=4.8 Hz), 8.36 (1H, s). [M+H] Calc'd for C₂₅H₂₅N₃O₃, 416; Found, 416.

Preparation 177a: methyl 3-({[(1R)-6-[(4-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 52% yield from Preparation 122a and 4-methoxy-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Example 177: 3-({[(1R)-6-[(4-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 84% yield from Preparation 177a according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.60-1.81 (4H, m), 2.59-2.63 (2H, m), 2.99-3.01 (1H, m), 3.13 (3H, s), 3.37-3.56 (2H, m), 3.72 (3H, s), 6.49-6.54 (2H, m), 6.87-6.90 (2H, m), 6.99-7.02 (2H, m), 7.09 (1H, d, J=8.4 Hz), 7.77 (1H, d, J=5.1 Hz), 7.87 (1H, d, J=5.4 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Preparation 178a: methyl 3-({[(4R)-7-[(4-methoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 51% yield from Preparation 126b and 4-methoxy-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₅H₂₇N₃O₄, 434; Found, 434.

Example 178: 3-({[(4R)-7-[(4-methoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 84% yield from Preparation 178a according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.80-1.94 (2H, m), 2.97-3.01 (1H, m), 3.11 (3H, s), 3.31-3.38 (1H, m), 3.41-3.46 (1H, m), 3.73 (3H, s), 4.04-4.12 (2H, m), 6.08 (1H, s), 6.22-6.25 (1H, m), 6.89-6.92 (2H, m), 7.02-7.07 (3H, m), 7.56 (1H, d, J=4.8 Hz), 7.82 (1H, d, J=5.1 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₄H₂₅N₃O₄, 420; Found, 420.

Preparation 179a: methyl 3-({[(4R)-7-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 35% yield from Preparation 126b and N-methyl-4-(pyrrolidin-1-yl)aniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₈H₃₂N₄O₃, 473; Found, 473.

Example 179: 3-({[(4R)-7-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 87% yield from Preparation 179a according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.79-1.80 (1H, m), 1.86-1.87 (5H, m), 2.97-2.98 (1H, m), 3.25-3.26 (3H, m), 3.38-3.39 (4H, m), 3.40-3.43 (1H, m), 3.55-3.56 (1H, m), 3.59-3.61 (2H, m), 5.96-5.97 (1H, m) 6.12-6.14 (1H, m), 6.52-6.56 (2H, m), 6.99-7.02 (3H, m), 7.53-7.55 (1H, d, J=4.8 Hz), 7.80-7.82 (1H, d, J=5.1 Hz), 8.36 (1H, s). [M+H] Calc'd for C₂₇H₃₀N₄O₃, 459; Found, 459.

Preparation 180a: 1-(4-nitrophenyl)azetidine

1-Fluoro-4-nitrobenzene (5.0 g, 35.5 mmol) was added to a suspension of azetidine HCl (3.98 g, 42.55 mmol) and K₂CO₃ (7.34 g, 53.19 mmol) in EtOH (100 mL) at r.t., and the reaction was stirred at 40° C. overnight. The reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=10:1) to give compound 700 mg (11%) of the title compound as a yellow solid. [M+H] Calc'd for C₉H₁₀N₂O₂, 180; Found, 180.

Preparation 180b: 4-(azetidin-1-yl)aniline

10% Pd/C (70 mg) was added to a solution of 1-(4-nitrophenyl)azetidine (0.7 g, 3.9 mmol) in EtOH (15 mL) at r.t. under N₂. After stirring under 50 psi H₂ overnight, the reaction mixture was filtered through Celite and concentrated to give 580 mg (99%) of the title compound as a brown oil. [M+H] Calc'd for C₉H₁₂N₂, 149; Found, 149.

Preparation 180c: 4-(azetidin-1-yl)-N-methylaniline

The title compound was prepared in 73% overall yield from 4-(azetidin-1-yl)aniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₁₀H₁₄N₂, 163; Found, 163.

Preparation 180d: methyl 3-({[(1R)-6-{[4-(azetidin-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 50% yield from Preparation 122a and 4-(azetidin-1-yl)-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₈H₃₂N₄O₂, 457; Found, 457.

Example 180: 3-({[(1R)-6-{[4-(azetidin-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 73% yield from Preparation 180d according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.59-1.64 (1H, m) 1.70-1.81 (3H, m), 2.24-2.29 (2H, m), 2.56-2.60 (2H, m), 2.95-3.06 (1H, m), 3.11 (3H, s), 3.30-3.42 (1H, m), 3.48-3.52 (1H, m), 3.3-3.79 (4H, m), 6.42-6.45 (4H, m), 6.93-6.95 (2H, m), 7.06-7.08 (1H, m), 7.57 (1H, d, J=4.5 Hz), 7.83 (1H, d, J=5.1 Hz), 8.34 (1H, s). [M+H] Calc'd for C₂₇H₃₀N₄O₂, 443; Found, 443.

Preparation 181a: N-methyl-4-(trifluoromethoxy)aniline

The title compound was prepared in 68% overall yield from 4-(trifluoromethoxy)aniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₈H₈F₃NO, 192; Found, 192.

Preparation 181b: methyl 3-({[(1R)-6-{methyl[4-(trifluoromethoxy)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 67% yield from Preparation 122a and N-methyl-4-(trifluoromethoxy)aniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₆H₂₆F₃N₃O₃, 486; Found, 486.

Example 181: 3-({[(1R)-6-{methyl[4-(trifluoromethoxy)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 94% yield from Preparation 181b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.63-1.84 (4H, m), 2.65-2.69 (2H, m), 3.18-3.20 (1H, m), 3.25 (3H, s) 3.40-3.47 (1H, m), 3.55-3.61 (1H, m), 6.85-6.88 (4H, m), 7.16 (2H, d, J=8.7 Hz), 7.29 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=5.1 Hz), 7.82 (1H, d, J=5.1 Hz), 8.35 (1H, s). [M+H] Calc'd for C₂₅H₂₄F₃N₃O₃, 472; Found, 472.

Preparation 182a: methyl 3-({[(4R)-7-{methyl[4-(trifluoromethoxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 32% yield from Preparation 126b and N-methyl-4-(trifluoromethoxy)aniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₅H₂₄F₃N₃O₄, 488; Found, 488.

Example 182: 3-({[(4R)-7-{methyl[4-(trifluoromethoxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 89% yield from Preparation 182a according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.87-1.98 (2H, m), 3.05-3.10 (1H, m), 3.24 (3H, s), 3.44-3.51 (1H, m), 3.64-3.70 (1H, m), 4.12-4.19 (2H, m), 6.45 (1H, d, J=2.4 Hz), 6.55-6.59 (1H, m), 6.94-6.96 (2H, m), 7.18-7.26 (3H, m), 7.55 (1H, d, J=5.1 Hz), 7.82 (1H, d, J=5.1 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₄H₂₂F₃N₃O₄, 474; Found, 474.

Preparation 183a: methyl 3-({[(4R)-7-{[4-(azetidin-1-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 51% yield from Preparation 126b and 4-(azetidin-1-yl)-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₃₀N₄O₃, 459; Found, 459.

Example 183: 3-({[(4R)-7-{[4-(azetidin-1-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 81% yield from Preparation 183a according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.82-1.95 (2H, m), 2.24-2.31 (2H, m), 2.94-2.97 (1H, m), 3.07 (3H, s), 3.29-3.37 (1H, m), 3.50-3.58 (1H, m), 3.74-3.79 (4H, m), 4.02-4.13 (2H, m), 5.99 (1H, d, J=2.4 Hz), 6.16 (1H, dd, J=8.7 Hz, 2.4 Hz), 6.40 (2H, d, J=8.4 Hz), 6.94 (2H, d, J=8.7 Hz), 7.03 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=4.8 Hz), 7.77 (1H, d, J=4.8 Hz), 8.25 (1H, s). [M+H] Calc'd for C₂₆H₂₈N₄O₃, 445; Found, 445.

Preparation 184a: 4-(difluoromethoxy)-N-methylaniline

The title compound was prepared in 82% yield from 4-(difluoromethoxy)aniline according to the general procedure outlined for Preparation 127a. ¹H NMR (400 MHz, CDCl₃): δ 2.82 (3H, s), 3.75 (1H, br s), 6.37 (1H, t, J=75.0 Hz), 6.56 (2H, d, J=7.1 Hz), 6.98 (2H, d, J=8.4 Hz). [M+H] Calc'd for C₈H₉F₂NO, 174; Found, 174.

Preparation 184b: tert-butyl N-{[(1R)-6-{[4-(difluoromethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 59% yield from Preparation 6d and Preparation 184a according to the general procedure outlined for Preparation 9a. [M+H] Calc'd for C₂₄H₃₀F₂N₂O₃, 433; Found, 433.

Preparation 184c: (5R)-5-(aminomethyl)-N-[4-(difluoromethoxy)phenyl]-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation 184b according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₉H₂₂F₂N₂O, 333; Found, 333.

Preparation 184d: methyl 3-({[(1R)-6-{[4-(difluoromethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 76% yield from Preparation 184c according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₆H₂₇F₂N₃O₃, 468; Found, 468.

Example 184: 3-({[(1R)-6-{[4-(difluoromethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 84% yield from Preparation 184d according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.64-1.91 (4H, m), 2.65-2.70 (2H, m), 3.03-3.07 (1H, m), 3.32 (3H, s), 3.40-3.46 (1H, m), 3.54-3.59 (1H, m), 6.76-6.80 (2H, m), 6.90-7.28 (6H, m), 7.56 (1H, d, J=4.5 Hz), 7.77 (1H, br s), 7.82 (1H, d, J=4.5 Hz), 8.33 (1H, s). [M+H] Calc'd for C₂₅H₂₅F₂N₃O₃, 454; Found, 454.

Preparation 185a: 4-ethoxy-N-methylaniline

The title compound was prepared in 61% overall yield from 4-ethoxyaniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₉H₁₃NO, 152; Found, 152.

Preparation 185b: methyl 3-({[(1R)-6-[(4-ethoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 122a and 4-ethoxy-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₃₁N₃O₃, 446; Found, 446.

Example 185: 3-({[(1R)-6-[(4-ethoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 33% yield from Preparation 185b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.32 (3H, t, J=6.9 Hz), 1.62-1.78 (4H, m), 2.62-2.63 (2H, m), 2.95-2.97 (1H, m), 3.15 (3H, s), 3.26-3.33 (1H, m), 3.45-3.51 (1H, m), 3.99 (2H, q, J=6.9 Hz), 6.51-6.57 (2H, m), 6.88 (2H, d, J=8.7 Hz), 7.00 (2H, d, J=8.7 Hz), 7.12 (1H, d, J=8.4 Hz), 7.57 (1H, d, J=5.1 Hz), 7.77 (1H, d, J=5.1 Hz), 8.20 (1H, s). [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Preparation 186a: methyl 3-({[(4R)-7-[(4-ethoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 58% yield from Preparation 126b and 4-ethoxy-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₆H₂₉N₃O₄, 448; Found, 448.

Example 186: 3-({[(4R)-7-[(4-ethoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 94% yield from Preparation 186a according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.32 (3H, t, J=6.8 Hz), 1.81-1.84 (1H, m), 1.92-1.98 (1H, m), 2.99-3.02 (1H, m), 3.13 (3H, s), 3.39-3.45 (1H, m), 3.59-3.63 (1H, m), 4.00 (2H, q, J=6.8 Hz), 4.06-4.16 (2H, m), 6.10 (1H, d, J=2.0 Hz), 6.25 (2H, dd, J=8.8 Hz, 2.0 Hz), 6.91 (2H, d, J=8.8 Hz), 7.04 (2H, d, J=8.8 Hz), 7.07 (2H, d, J=8.8 Hz), 7.03-7.09 (3H, m), 7.56 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=4.8 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₄, 434; Found, 434.

Preparation 187a: N-methyl-4-(propan-2-yl)aniline

A mixture of 1-bromo-4-isopropylbenzene (1.0 g, 5.03 mmol), methylamine (25 mL, 50.0 mmol), CuI (1.15 g, 6.0 mmol), KOAc (1.24 g, 12.6 mmol) and DMF (30 mL) in a sealed tube under N₂ was heated to 100° C. overnight. The mixture was cooled to r.t., diluted with water (100 mL), and extracted with EtOAc. The organic layer was dried (Na₂SO₄), concentrated, and purified by silica gel chromatography (PE:EtOAc=10:1) to give 254 mg (34%) of the title compound as a yellow oil. [M+H] Calc'd for C₁₀H₁₅N, 150; Found, 150.

Preparation 187b: methyl 3-({[(4R)-7-{methyl[4-(propan-2-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 57% yield from Preparation 126b and N-methyl-4-(propan-2-yl)aniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₃₁N₃O₃, 446; Found, 446.

Example 187: 3-({[(4R)-7-{methyl[4-(propan-2-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 90% yield from Preparation 187b according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.19 (6H, d, J=6.8 Hz), 1.83-1.99 (2H, m), 2.81-2.88 (1H, m), 3.02-3.05 (1H, m), 3.17 (3H, s), 3.44-3.48 (1H, m), 3.62-3.66 (1H, m), 4.09-4.19 (2H, m), 6.25 (1H, d, J=1.6 Hz), 6.40 (1H, dd, J=8.4 Hz, 1.6 Hz), 6.97 (2H, d, J=8.0 Hz), 7.13 (1H, d, J=8.4 Hz), 7.17 (2H, d, J=8.0 Hz), 7.57 (1H, d, J=5.2 Hz), 7.83 (1H, d, J=5.2 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Preparation 188a: N-methyl-4-(1H-pyrazol-1-yl)aniline

The title compound was prepared in 98% overall yield from 4-(1H-pyrazol-1-yl)aniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₁₀H₁₁N₃, 174; Found, 174.

Preparation 188b: methyl 3-({[(1R)-6-{methyl[4-(1H-pyrazol-1-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 32% yield from Preparation 122a and N-methyl-4-(1H-pyrazol-1-yl)aniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₈H₂₉N₅O₂, 468; Found, 468.

Example 188: 3-({[(1R)-6-{methyl[4-(1H-pyrazol-1-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 57% yield from Preparation 188b according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.64-1.69 (1H, m), 1.79-1.85 (3H, m), 2.67-2.70 (2H, m), 3.07-3.08 (1H, m), 3.26 (3H, s), 3.42-3.47 (1H, m), 3.57-3.61 (1H, m), 6.49 (1H, s), 6.84 (1H, s), 6.86 (1H, d, J=8.4 Hz), 6.99 (2H, d, J=8.8 Hz), 7.27 (1H, d, J=8.4 Hz), 7.57 (1H, d, J=4.8 Hz), 7.66 (2H, d, J=8.8 Hz), 7.68 (1H, s), 7.83 (1H, d, J=4.8 Hz), 8.35 (2H, s). [M+H] Calc'd for C₂₇H₂₇N₅O₂, 454; Found, 454.

Preparation 189a: methyl 3-({[(4R)-7-{methyl[4-(1H-pyrazol-1-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 52% yield from Preparation 126b and N-methyl-4-(1H-pyrazol-1-yl)aniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₂₇N₅O₃, 470; Found, 470.

Example 189: 3-({[(4R)-7-{methyl[4-(1H-pyrazol-1-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 83% yield from Preparation 189a according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.85-1.90 (1H, m), 1.97-2.02 (1H, m), 3.07-3.10 (1H, m), 3.24 (3H, s), 3.46-3.52 (1H, m), 3.66-3.71 (1H, m), 4.11-4.22 (2H, m), 6.43 (1H, s), 6.50 (1H, s), 6.55 (1H, d, J=8.4 Hz), 7.08 (2H, d, J=8.8 Hz), 7.23 (1H, d, J=8.4 Hz), 7.57 (1H, d, J=5.2 Hz), 7.69 (1H, s), 7.70 (2H, d, J=8.8 Hz), 7.85 (1H, d, J=5.2 Hz), 8.38 (1H, s), 8.41 (1H, s). [M+H] Calc'd for C₂₆H₂₅N₅O₃, 456; Found, 456.

Preparation 190a: 4-(difluoromethoxy)-N-methylaniline

The title compound was prepared in 29% overall yield from 4-(difluoromethoxy)aniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₈H₉F₂NO, 174; Found, 174.

Preparation 190b: methyl 3-({[(4R)-7-{[4-(difluoromethoxy)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 75% yield from Preparation 126b and 4-(difluoromethoxy)-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₅H₂₅F₂N₃O₄, 470; Found, 470.

Example 190: 3-({[(4R)-7-{[4-(difluoromethoxy)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 89% yield from Preparation 190b according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.83-1.87 (1H, m), 1.94-2.01 (1H, m), 3.04-3.08 (1H, m), 3.19 (3H, s), 3.43-3.49 (1H, m), 3.63-3.68 (1H, m), 4.10-4.20 (2H, m), 6.34 (1H, s), 6.47 (1H, d, J=8.0 Hz), 7.03 (2H, d, J=8.8 Hz), 7.10 (2H, d, J=8.8 Hz), 7.13 (1H, t, J=74.8 Hz), 7.19 (1H, d, J=8.8 Hz), 7.57 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=4.8 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₄H₂₃F₂N₃O₄, 456; Found, 456.

Preparation 191a: tert-butyl N-{[(1R)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 69% yield from Preparation 6d and N-methylaniline according to the general procedure for Preparation 9a. [M+H] Calc'd for C₂₃H₃₀N₂O₂, 367; Found, 367.

Preparation 191b: (5R)-5-(aminomethyl)-N-methyl-N-phenyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in 96% yield from Preparation 191a according to the procedure for Preparation 43b. [M+H] Calc'd for C₁₈H₂₂N₂, 267; Found, 267.

Preparation 191c: 6-chloro-3-({[(1R)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridazine-4-carboxylic Acid

A 0.3 M solution of Preparation 191b (132 mg, 0.5 mmol) in 1-butanol was combined with 3,6-dichloropyridazine-4-carboxylic acid (97 mg, 0.5 mmol) and DIEA (304 μL, 1.8 mmol). The reaction mixture was capped and heated to 80° C. for 14 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with saturated bicarbonate solution (30 mL) and brine (30 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The resulting orange solid (190 mg) was carried forward without any further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 1.59-1.90 (m, 4H) 2.62-2.73 (m, 2H) 3.10-3.17 (m, 1H) 3.22 (s, 3H) 3.56-3.69 (m, 1H) 3.80-3.92 (m, 1H) 6.76-6.94 (m, 5H) 7.19-7.27 (m, 3H) 7.75-7.79 (m, 1H) 8.15-8.28 (m, 1H). [M+H] Calc'd for C₂₃H₂₃ClN₄O₂, 423; Found, 423.

Example 191: 3-({[(1R)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridazine-4-carboxylic Acid

A solution of Preparation 191c (171 mg, 0.4 mmol) in MeOH (7.1 mL) was treated with ammonium formate (51 mg, 0.8 mmol), and 10% Pd/C (Degussa) (25 mg). The reaction mixture was heated to 50° C. using microwave irradiation for 2 h. The crude reaction mixture was filtered through a short plug of Celite, washing with MeOH (˜30 mL). The resulting filtrate was concentrated in vacuo. The residue was diluted with EtOAc (25 ml), washed with water, dried (MgSO₄), filtered, and concentrated in vacuo. The resulting residue was purified by prep-HPLC to give 21 mg (14%) of the title compound as a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.61-1.91 (m, 4H) 2.61-2.74 (m, 2H) 3.06-3.18 (m, 1H) 3.22 (s, 3H) 3.53-3.68 (m, 1H) 3.85-3.96 (m, 1H) 6.75-6.89 (m, 3H) 6.89-6.95 (m, 2H) 7.19-7.28 (m, 3H) 7.67-7.75 (m, 1H) 8.10-8.17 (m, 1H) 8.57-8.63 (m, 1H). [M+H] Calc'd for C₂₃H₂₄N₄O₂, 389; Found, 389.

Preparation 192a: N-methyl-4-(2,2,2-trifluoroethyl)aniline

The title compound was prepared in 77% yield from 1-bromo-4-(2,2,2-trifluoroethyl)benzene according to the procedure Preparation 187a. [M+H] Calc'd for C₉H₁₀F₃N, 190; Found, 190.

Preparation 192b: methyl 3-({[(4R)-7-{methyl[4-(2,2,2-trifluoroethyl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 47% yield from Preparation 126b and N-methyl-4-(2,2,2-trifluoroethyl)aniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₆H₂₆F₃N₃O₃, 486; Found, 486.

Example 192: 3-({[(4R)-7-{methyl[4-(2,2,2-trifluoroethyl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 88% yield from Preparation 192b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.84-1.88 (1H, m), 1.95-2.02 (1H, m), 3.06-3.10 (1H, m), 3.20 (3H, s), 3.46-3.58 (3H, m), 3.66-3.70 (1H, m), 4.11-4.22 (2H, m), 6.42 (1H, s), 6.54 (1H, d, J=8.8 Hz), 6.95 (2H, d, J=8.0 Hz), 7.20-7.23 (3H, m), 7.57 (1H, d, J=4.8 Hz), 7.85 (1H, d, J=4.8 Hz), 8.40 (1H, s). [M+H] Calc'd for C₂₅H₂₄F₃N₃O₃, 472; Found, 472.

Preparation 193a: 4-(1H-imidazol-1-yl)-N-methylaniline

The title compound was prepared in 33% overall yield from 4-(1H-imidazol-1-yl)aniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₁₀H₁₁N₃, 174; Found, 174.

Preparation 193b: methyl 3-({[(1R)-6-{[4-(1H-imidazol-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 43% yield from Preparation 122a and 4-(1H-imidazol-1-yl)-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₈H₂₉N₅O₂, 468; Found, 468.

Example 193: 3-({[(1R)-6-{[4-(1H-imidazol-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 82% yield from Preparation 193b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.64-1.69 (1H, m), 1.79-1.85 (3H, m), 2.66-2.71 (2H, m), 3.07-3.08 (1H, m), 3.26 (3H, s), 3.39-3.44 (1H, m), 3.56-3.60 (1H, m), 6.86-6.90 (2H, m), 6.97-6.99 (2H, m), 7.07 (1H, s), 7.30 (1H, d, J=6.3 Hz), 7.46 (2H, d, J=6.3 Hz), 7.57-7.62 (2H, m), 7.81 (1H, d, J=3.6 Hz), 8.11 (1H, s), 8.31 (1H, s). [M+H] Calc'd for C₂₇H₂₇N₅O₂, 454; Found, 454.

Preparation 194a: methyl 3-({[(4R)-7-{[4-(1H-imidazol-1-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 72% yield from Preparation 126b and 4-(1H-imidazol-1-yl)-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₂₇N₅O₃, 470; Found, 470.

Example 194: 3-({[(4R)-7-{[4-(1H-imidazol-1-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 81% yield from Preparation 194a according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.87-1.90 (1H, m), 1.98-2.00 (1H, m), 3.06-3.09 (1H, m), 3.25 (3H, s), 3.43-3.48 (1H, m), 3.64-3.69 (1H, m), 4.13-4.20 (2H, m), 6.46 (1H, s), 6.58 (1H, d, J=6.0 Hz), 7.04-7.08 (3H, m), 7.25 (1H, d, J=6.3 Hz), 7.50 (2H, d, J=6.3 Hz), 7.58 (1H, d, J=3.6 Hz), 7.64 (1H, s), 7.82 (1H, d, J=3.3 Hz), 8.13 (1H, s), 8.35 (1H, s). [M+H] Calc'd for C₂₆H₂₅N₅O₃, 456; Found, 456.

Preparation 195a: 4-(3,3-difluoroazetidin-1-yl)-N-methylaniline

The title compound was prepared in 10% overall yield from 3,3-difluoroazetidine hydrochloride according to the general scheme outlined for Preparations 180a, 180b, and 180c. [M+H] Calc'd for C₁₀H₁₂F₂N₂, 199; Found, 199.

Preparation 195b: methyl 3-({[(1R)-6-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 39% yield from Preparation 122a and 4-(3,3-difluoroazetidin-1-yl)-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₂₈F₂N₄O₂, 479; Found, 479.

Example 195: 3-({[(1R)-6-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 90% yield from Preparation 195b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.59-1.65 (1H, m), 1.76-1.81 (3H, m), 2.57-2.63 (2H, m), 2.96-3.01 (1H, m), 3.14 (3H, s), 3.33-3.41 (1H, m), 3.47-3.54 (1H, m), 4.24 (4H, t, J=12.3 Hz), 6.48 (1H, s), 6.51 (1H, d, J=8.8 Hz), 6.57 (2H, d, J=8.4 Hz), 7.00 (2H, d, J=8.4 Hz), 7.09 (1H, d, J=8.8 Hz), 7.55 (1H, d, J=4.8 Hz), 7.81 (1H, d, J=4.8 Hz), 8.32 (1H, s). [M+H] Calc'd for C₂₇H₂₈F₂N₄O₂, 479; Found, 479.

Preparation 196a: methyl 3-({[(4R)-7-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 35% yield from Preparation 126b and 4-(3,3-difluoroazetidin-1-yl)-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₂₈F₂N₄O₃, 495; Found, 495.

Example 196: 3-({[(4R)-7-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 86% yield from Preparation 196a according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.78-1.86 (1H, m), 1.90-1.98 (1H, m), 2.97-3.02 (1H, m), 3.12 (3H, s), 3.40-3.47 (1H, m), 3.59-3.65 (1H, m), 4.05-4.14 (2H, m), 4.25 (4H, t, J=12.0 Hz), 6.07 (1H, s), 6.23 (1H, d, J=6.6 Hz), 6.58 (2H, d, J=8.4 Hz), 7.03 (2H, d, J=8.4 Hz), 7.06 (1H, d, J=6.6 Hz), 7.56 (1H, d, J=3.9 Hz), 7.84 (1H, d, J=3.9 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₆H₂₆F₂N₄O₃, 481; Found, 481.

Preparation 197a: 4-(2-methoxyethoxy)-N-methylaniline

The title compound was prepared in 88% yield from 4-(2-methoxyethoxy)aniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₁₀H₁₅NO₂, 182; Found, 182.

Preparation 197b: tert-butyl N-{[(1R)-6-{[4-(2-methoxyethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 53% yield from Preparation 6d and Preparation 197a according to the general procedure outlined for Preparation 9a. [M+H] Calc'd for C₂₆H₃₆N₂O₄, 441; Found, 441.

Preparation 197c: (5R)-5-(aminomethyl)-N-[4-(2-methoxyethoxy)phenyl]-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation 197b according to the procedure for Preparation 43b. [M+H] Calc'd for C₂₁H₂₈N₂O₂, 341; Found, 341.

Preparation 197d: methyl 3-({[(1R)-6-{[4-(2-methoxyethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 52% yield from Preparation 197c according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₈H₃₃N₃O₄, 476; Found, 476.

Example 197: 3-({[(1R)-6-{[4-(2-methoxyethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 62% yield from Preparation 197d according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.60-1.79 (4H, m), 2.0-2.65 (2H, m), 2.98-3.02 (1H, m), 3.15 (3H, s), 3.30 (3H, s), 3.38-3.54 (2H, m), 3.65 (2H, s), 4.06 (2H, s), 6.51-6.58 (2H, m), 6.91 (2H, d, J=8.0 Hz), 7.00 (2H, d, J=7.8 Hz), 7.12 (1H, d, J=8.3 Hz), 7.56 (1H, br s), 7.82 (1H, br s), 7.84 (1H, br s), 8.32 (1H, br s), 13.4 (1H, br s). [M+H] Calc'd for C₂₇H₃₁N₃O₄, 462; Found, 462.

Preparation 198a: methyl 3-({[(4R)-7-(1-phenylethenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of 4,4,5,5-tetramethyl-2-(1-phenyl-vinyl)-[1,3,2]dioxaborolane (612 mg, 2.66 mmol), S-Phos (55 mg, 0.13 mmol), Pd(OAc)₂ (15 mg, 0.0665 mmol) and K₃PO₄ (708 mg, 3.33 mmol) in ACN/H₂O (30 mL/10 mL) was added Preparation 126b (500 mg, 1.33 mmol). The reaction mixture was stirred at 120° C. under N₂ overnight. The solvent was removed by vacuum, and the residue was purified by silica gel chromatography (PE:EtOAc=3:1) to give 200 mg (38%) of the title compound. [M+H] Calc'd for C₂₅H₂₄N₂O₃, 401; Found, 401.

Preparation 198b: methyl 3-({[(4R)-7-(1-phenylethyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

10% Pd/C (20 mg) was added to a solution of Preparation 198a (0.1 g, 0.25 mmol) in EtOH (15 mL) under N₂ at r.t. After stirring under 50 psi of H₂ overnight, the reaction mixture was filtered through Celite and concentrated. The residue was purified by prep-HPLC to give 50 mg (50%) of the title compound as a brown oil. [M+H] Calc'd for C₂₅H₂₆N₂O₃, 403; Found, 403.

Example 198: 3-({[(4R)-7-(1-phenylethyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 83% yield from Preparation 198b according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.52 (3H, d, J=7.2 Hz) 1.80-1.90 (1H, m), 1.91-1.99 (1H, m), 3.03-3.09 (1H, m), 3.43-3.49 (1H, m), 3.62-3.68 (1H, m), 4.04 (1H, t, J=7.2 Hz), 4.09-4.18 (2H, m), 6.64 (1H, s), 6.75 (1H, d, J=8.0 Hz), 7.14-7.29 (6H, m), 7.58 (1H, d, J=5.2 Hz), 7.84 (1H, d, J=5.2 Hz), 8.40 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₃, 389; Found, 389.

Preparation 199a: 5-isopropyl-N-methylpyridin-2-amine

A solution of 5-isopropyl-pyridin-2-ylamine (0.5 g, 3.67 mmol) in dry THF was purged with N₂ and cooled to −78° C. n-BuLi (1.62 mL, 4.04 mmol) was added dropwise. The reaction was stirred at 0° C. for 0.5 h, and then iodomethane (0.25 mL, 4.04 mmol) was added dropwise. The resulting mixture was stirred overnight while warming to r.t. Water (20 mL) was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na₂SO₄, concentrated, and purified by silica gel chromatography (10% to 30% EtOAc in PE) to give 200 mg (36%) of the title compound as a brown oil. [M+H] Calc'd for C₉H₁₄N₂, 151; Found, 151.

Preparation 199b: methyl 3-({[(4R)-7-{methyl[5-(propan-2-yl)pyridin-2-yl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 65% yield from Preparation 126b and 5-isopropyl-N-methylpyridin-2-amine according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₆H₃₀N₄O₃, 447; Found, 447.

Example 199: 3-({[(4R)-7-{methyl[5-(propan-2-yl)pyridin-2-yl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 82% yield from Preparation 199b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.16 (6H, d, J=7.2 Hz), 1.85-1.93 (1H, m), 1.95-2.06 (1H, m), 2.73-2.84 (1H, m), 3.09-3.16 (1H, m), 3.32 (3H, s), 3.48-3.56 (1H, m), 3.69-3.75 (1H, m), 4.12-4.26 (2H, m), 6.57 (1H, d, J=8.1 Hz), 6.64 (1H, d, J=2.4 Hz), 6.74 (1H, dd, J=8.1 Hz, 1.8 Hz), 7.32 (1H, d, J=8.4 Hz), 7.36 (1H, dd, J=8.4 Hz, 2.4 Hz), 7.57 (1H, d, J=5.1 Hz), 7.85 (1H, d, J=5.1 Hz), 8.04 (1H, d, J=1.8 Hz), 8.42 (1H, s). [M+H] Calc'd for C₂₅H₂₈N₄O₃, 433; Found, 433.

Preparation 200a: methyl 3-({[(1R)-6-{methyl[4-(trifluoromethanesulfonyloxy)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 165c (576 mg, 1.37 mmol) and pyridine (217 mg, 2.75 mmol) in THF (10 mL) was added Tf₂O (407 mg, 1.44 mmol) slowly at 0° C. The mixture was stirred at rt for 2 h. The mixture was concentrated and purified by silica gel chromatography (PE:EtOAc=2:1) to give 553 mg (73%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₆H₂₆F₃N₃O₅S, 550; Found, 550.

Preparation 200b: methyl 3-({[(1R)-6-[(4-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}phenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 55% yield from Preparation 200a and 3-[(tert-butyldimethylsilanyl)oxy]azetidine according to the procedure for Preparation 126c. [M+H] Calc'd for C₃₄H₄₆N₄O₃Si, 587; Found, 587.

Preparation 200c: methyl 3-({[(1R)-6-{[4-(3-hydroxyazetidin-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 89% yield from Preparation 200b according to the procedure for Preparation 165c. [M+H] Calc'd for C₂₈H₃₂N₄O₃, 473; Found, 473.

Example 200: 3-({[(1R)-6-{[4-(3-hydroxyazetidin-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 95% yield from Preparation 200c according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.58-1.79 (4H, m), 2.56-2.60 (2H, m), 2.92-2.95 (1H, m), 3.09 (3H, s) 3.26-3.32 (1H, m), 3.35-3.58 (4H, m), 4.02 (2H, t, J=6.6 Hz), 4.50-4.54 (1H, m), 6.39-6.45 (4H, m), 6.92 (2H, d, J=6.0 Hz), 7.05 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=5.1 Hz), 7.78 (1H, d, J=4.8 Hz), 8.26 (1H, s). [M+H] Calc'd for C₂₇H₃₀N₄O₃, 459; Found, 459.

Preparation 201a: methyl 3-({[(4R)-7-{[4-(3,6-dihydro-2H-pyran-4-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 49% yield from Preparation 126b and Preparation 174a according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₉H₃₁N₃O₄, 486; Found, 486.

Example 201: 3-({[(4R)-7-{[4-(3,6-dihydro-2H-pyran-4-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 83% yield from Preparation 201a according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.86-1.98 (2H, m), 2.38-2.40 (2H, m), 3.03-3.08 (1H, m), 3.19 (3H, s), 3.42-3.50 (1H, m), 3.63-3.68 (1H, m), 3.77-3.80 (2H, m), 4.11-4.19 (4H, m), 6.12 (1H, m), 6.39 (1H, d, J=2.1 Hz), 6.50-6.53 (1H, m), 6.93 (2H, d, J=8.7 Hz), 7.18 (1H, d, J=8.1 Hz), 7.33 (2H, d, J=8.1 Hz), 7.55 (1H, d, J=4.8 Hz), 7.82 (1H, d, J=5.1 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₈H₂₉N₃O₄, 472; Found, 472.

Preparation 202a: methyl 3-({[(4R)-7-{methyl[4-(oxan-4-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 42% yield from Preparation 126b and Preparation 175a according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₉H₃₃N₃O₄, 488; Found, 488.

Example 202: 3-({[(4R)-7-{methyl[4-(oxan-4-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 96% yield from Preparation 202a according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.59-1.67 (4H, m), 1.85-1.94 (2H, m), 2.67-2.70 (1H, m), 3.00-3.04 (1H, m), 3.22 (3H, s), 3.39-3.46 (3H, m), 3.59-3.65 (1H, m), 3.90-3.94 (2H, m), 4.09-4.14 (2H, m), 6.26 (1H, d, J=2.8 Hz), 6.27-6.43 (1H, m), 6.94-6.97 (2H, m), 7.12-7.17 (3H, m), 7.54 (1H, d, J=4.8 Hz), 7.80 (1H, d, J=4.8 Hz), 8.34 (1H, s). [M+H] Calc'd for C₂₈H₃₁N₃O₄, 474; Found, 474.

Preparation 203a: tert-butyl N-{[(4R)-7-(1-phenylethenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 87% yield from Preparation 18d and 4,4,5,5-tetramethyl-2-(1-phenyl-vinyl)-[1,3,2]dioxaborolane according to the procedure for Preparation 198a. Calc'd for C₂₂H₂₇NO₃, 309; Found, 309.

Preparation 203b: tert-butyl N-{[(4R)-7-(1-phenylcyclopropyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

A solution of Preparation 203a (0.2 g, 0.548 mmol) in DCE (5 mL) was purged with N₂ and cooled to 0° C. Diethyl zinc (3.3 mL, 3.3 mmol) was added to the reaction mixture dropwise. After stirring for 10 min, diiodomethane (1.76 g, 6.576 mmol) was added dropwise. The reaction mixture was stirred overnight while warming to r.t. Water (10 mL) was added, and the mixture was extracted with EtOAc. The organic layer was dried (Na₂SO₄) and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=10:1) to give 13 mg (6%) of the title compound as a brown oil. Calc'd for C₂₄H₂₉NO₃, 323; Found, 323.

Preparation 203c: [(4R)-7-(1-phenylcyclopropyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

A mixture of Preparation 203b (30 mg) in HCl solution (2.0 M in EtOAc, 10 mL) was stirred for 2 h at r.t. The solution was concentrated and used for next reaction without further purification. Calc'd for C₁₉H₂₁NO, 263; Found, 263.

Preparation 203d: methyl 3-({[(4R)-7-(1-phenylcyclopropyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 40% yield from Preparation 203c according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₆H₂₆N₂O₃, 415; Found, 415.

Example 203: 3-({[(4R)-7-(1-phenylcyclopropyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 63% yield from Preparation 203d according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.19 (4H, s), 1.80-1.87 (1H, m), 1.91-2.01 (1H, m), 3.04-3.09 (1H, m) 3.42-3.51 (1H, m), 3.62-3.69 (1H, m), 4.08-4.20 (2H, m), 6.57 (1H, d, J=1.8 Hz), 6.70 (1H, dd, J=7.8 Hz, 1.8 Hz), 7.15-7.30 (6H, m), 7.57 (1H, d, J=5.1 Hz), 7.84 (1H, d, J=5.1 Hz), 8.40 (1H, s). [M+H] Calc'd for C₂₅H₂₄N₂O₃, 401; Found, 401.

Preparation 204a: N-methyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline

The title compound was prepared in 37% yield, using 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester, according to the general procedure for the preparation of Preparation 174a. [M+H] Calc'd for C₁₃H₁₈N₂, 203; Found, 203.

Preparation 204b: methyl 3-({[(4R)-7-{methyl[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 20% yield from Preparation 126b and Preparation 204a according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₃₀H₃₄N₄O₃, 499; Found, 499.

Example 204: 3-({[(4R)-7-{methyl[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 16% yield from Preparation 204b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.82-1.98 (m, 2H), 2.77-3.04 (m, 6H), 3.04-3.08 (m, 1H), 3.20 (s, 3H), 3.30-3.76 (m, 5H), 4.11-4.16 (m, 2H), 6.05 (s, 1H), 6.43 (d, 1H, J=2.1 Hz), 6.55 (dd, 1H, J=2.1 Hz, 8.1 Hz), 6.91 (d, 2H, J=8.7 Hz), 7.21 (d, 1H, J=7.8 Hz), 7.35 (d, 2H, J=8.7 Hz), 7.55 (d, 1H, J=5.4 Hz), 7.81 (d, 1H, J=4.8 Hz), 8.36 (s, 1H). [M+H] Calc'd for C₂₉H₃₂N₄O₃, 485; Found, 485.

Preparation 205a: N-methyl-4-(1-methylpiperidin-4-yl)aniline

The title compound was prepared in 90% yield from Preparation 204a according to the general procedure for Preparation 175a. [M+H] Calc'd for C₁₃H₂₀N₂, 205; Found, 205.

Preparation 205b: methyl 3-({[(4R)-7-{methyl[4-(1-methylpiperidin-4-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 18% yield from Preparation 126b and Preparation 205a according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₃₀H₃₆N₄O₃, 501; Found, 501.

Example 205: 3-({[(4R)-7-{methyl[4-(1-methylpiperidin-4-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 14% yield from Preparation 205b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.90-1.93 (m, 6H), 2.72 (s, 3H), 3.00-3.03 (m, 3H), 3.16 (s, 3H), 3.39-3.61 (m, 5H), 4.09-4.10 (m, 2H), 6.29 (d, 1H, J=2.1 Hz), 6.43 (dd, 1H, J=2.1, 8.7 Hz), 6.96 (d, 2H, J=8.4 Hz), 7.14 (d, 3H, J=8.7 Hz), 7.56 (d, 1H, J=5.4 Hz), 7.82 (d, 1H, J=5.1 Hz), 8.36 (s, 1H). [M+H] Calc'd for C₂₉H₃₄N₄O₃, 487; Found, 487.

Preparation 206a: N,3,4-trimethylaniline

The title compound was prepared in 33% overall yield from 3,4-dimethylaniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₉H₁₃N, 136; Found, 136.

Preparation 206b: methyl 3-({[(4R)-7-[(3,4-dimethylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 43% yield from Preparation 126b and N,3,4-trimethylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Example 206: 3-({[(4R)-7-[(3,4-dimethylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 87% yield from Preparation 206b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.79-1.97 (2H, m), 2.16 (6H, s) 2.99-3.03 (1H, m), 3.13 (3H, s), 3.39-3.48 (1H, m), 3.59-3.65 (1H, m), 4.05-4.17 (2H, m), 6.19 (1H, d, J=2.4 Hz), 6.32-6.36 (1H, m), 6.75-6.79 (1H, m), 6.85 (1H, d, J=1.8 Hz), 7.03-7.10 (2H, m), 7.54 (1H, d, J=4.8 Hz), 7.82 (1H, d, J=4.8 Hz), 8.36 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Preparation 207a: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)aniline

The title compound was prepared in quantitative yield from 2-(4-aminophenyl)ethan-1-ol according to the procedure for Preparation 165a. [M+H] Calc'd for C₁₄H₂₅NOSi, 252; Found, 252.

Preparation 207b: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-methylaniline

The title compound was prepared in 49% overall yield from 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)aniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₁₅H₂₇NOSi, 266; Found, 266.

Preparation 207c: methyl 3-({[(4R)-7-[(4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}phenyl)-(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 39% yield from Preparation 126b and Preparation 207b according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₃₂H₄₃N₃O₄Si, 562; Found, 562.

Preparation 207d: methyl 3-({[(4R)-7-{[4-(2-hydroxyethyl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 80% yield from Preparation 207c according to the procedure for Preparation 165c. [M+H] Calc'd for C₂₆H₂₉N₃O₄, 448; Found, 448.

Example 207: 3-({[(4R)-7-{[4-(2-hydroxyethyl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 95% yield from Preparation 207d according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.79-1.95 (2H, m), 2.65 (2H, t, J=7.2 Hz), 3.01-3.04 (1H, m), 3.12 (3H, s) 3.43-3.48 (1H, m), 3.53-3.66 (3H, m), 4.08-4.15 (2H, m), 6.24 (1H, d, J=2.4 Hz), 6.37-6.40 (1H, m), 6.92-6.95 (2H, m), 7.11-7.13 (3H, m), 7.56 (1H, d, J=5.1 Hz), 7.83 (1H, d, J=4.8 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₄, 434; Found, 434.

Preparation 208a: N-methyl-4-propylaniline

The title compound was prepared in 95% overall yield from 4-propylaniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₁₀H₁₅N, 150; Found, 150.

Preparation 208b: methyl 3-({[(4R)-7-[methyl(4-propylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 24% yield from Preparation 126b and N-methyl-4-propylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₃₁N₃O₃, 446; Found, 446.

Example 208: 3-({[(4R)-7-[methyl(4-propylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 88% yield from Preparation 208b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 0.89 (3H, t, J=7.2 Hz), 1.50-1.63 (2H, m), 1.81-1.87 (1H, m), 1.91-2.01 (1H, m), 2.99-3.12 (1H, m), 3.17 (3H, s), 3.40-3.50 (3H, m), 3.61-3.68 (1H, m), 4.06-4.21 (2H, m), 6.25 (1H, d, J=2.4 Hz), 6.40 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.96 (2H, d, J=8.4 Hz), 7.11 (2H, d, J=8.4 Hz), 7.13 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=5.1 Hz), 7.84 (1H, d, J=5.1 Hz), 8.39 (1H, s). [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Preparation 209a: tert-butyl N-{[(1R)-6-{[4-(cyclopropylmethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 66% yield from 4-(cyclopropylmethoxy)-N-methylaniline and Preparation 6d according to the general procedure outlined for Preparation 9a. [M+H] Calc'd for C₂₇H₃₆N₂O₃, 437; Found, 437.

Preparation 209b: (5R)-5-(aminomethyl)-N-[4-(cyclopropylmethoxy)phenyl]-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation 209a according to the procedure for Preparation 43b. [M+H] Calc'd for C₂₂H₂₈N₂O, 337; Found, 337.

Preparation 209c: methyl 3-({[(1R)-6-{[4-(cyclopropylmethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 72% yield from Preparation 209b according to the procedure for Preparation 4d. [M+H] Calc'd for C₂₉H₃₃N₃O₃, 472; Found, 472.

Example 209: 3-({[(1R)-6-{[4-(cyclopropylmethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 89% yield from Preparation 209c according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 0.24 (2H, s), 0.49 (2H, d, J=6.0 Hz), 1.11-1.17 (1H, m), 1.52-1.58 (1H, m), 1.68-1.75 (3H, m), 2.53-2.58 (2H, m), 2.90-2.95 (1H, s), 3.07 (3H, s), 3.25-3.46 (2H, m), 3.71 (2H, d, J=6.7 Hz), 6.43 (1H, s), 6.48 (1H, d, J=7.4 Hz), 6.81 (2H, d, J=8.4 Hz), 6.92 (2H, d, J=8.4 Hz), 7.04 (1H, d, J=8.2 Hz), 7.50 (1H, s), 7.74 (1H, s), 8.22 (1H, s). [M+H] Calc'd for C₂₈H₃₁N₃O₃, 458; Found, 458.

Preparation 210a: 4-isopropoxy-N-methylaniline

The title compound was prepared in 96% overall yield from 4-isopropoxyaniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₁₀H₁₅NO, 166; Found, 166.

Preparation 210b: methyl 3-({[(4R)-7-{methyl[4-(propan-2-yloxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 45% yield from Preparation 126b and 4-isopropoxy-N-methylaniline according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₃₁N₃O₄, 462; Found, 462.

Example 210: 3-({[(4R)-7-{methyl[4-(propan-2-yloxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 78% yield from Preparation 210b according to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ 1.26 (6H, d, J=6.0 Hz), 1.79-1.86 (1H, m), 1.91-2.01 (1H, m), 2.97-3.05 (1H, m), 3.13 (3H, s), 3.40-3.46 (1H, m), 3.59-3.64 (1H, m), 4.05-4.17 (2H, m), 4.50-4.60 (1H, m), 6.10 (1H, d, J=2.4 Hz), 6.26 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.89 (2H, d, J=8.4 Hz), 7.02 (2H, d, J=8.4 Hz), 7.08 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=5.2 Hz), 7.83 (1H, d, J=5.2 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₆H₂₉N₃O₄, 448; Found, 448.

Preparation 211a: 1-(cyclopropylmethoxy)-4-nitrobenzene

4-Nitrophenol (5.0 g, 35.9 mmol) was added to a suspension of (bromomethyl)cyclopropane (10.7 g, 79.07 mmol) and K₂CO₃ (19.9 g, 143.76 mmol) in DMF (80 mL), and the reaction was stirred at 40° C. overnight. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL×3). Organics were washed with brine (50 mL), dried (Na₂SO₄), and concentrated. The residue was purified by silica gel chromatography (0-5% EtOAc/PE) to give 6.77 g (98%) of the title compound as a colorless oil. [M+H] Calc'd for C₁₀H₁₁NO₃, 194; Found, 194.

Preparation 211b: 4-(cyclopropylmethoxy)aniline

10% Pd/C (680 mg) was added to a solution of Preparation 211a (6.77 g, 35.1 mmol) in EtOAc (70 mL) under N₂, and the reaction mixture stirred under H₂ at r.t. overnight. The reaction mixture was filtered through Celite and concentrated to give 5.72 g (100%) of the title compound as a brown oil. [M+H] Calc'd for C₁₀H₁₃NO, 164; Found, 164.

Preparation 211c: 4-(cyclopropylmethoxy)-N-methylaniline

The title compound was prepared in 91% overall yield from Preparation 211b according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₁₁H₁₅NO, 178; Found, 178.

Preparation 211d: methyl 3-({[(4R)-7-{[4-(cyclopropylmethoxy)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 55% yield from Preparation 126b and Preparation 211c according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₈H₃₁N₃O₄, 474; Found, 474.

Example 211: 3-({[(4R)-7-{[4-(cyclopropylmethoxy)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 89% yield from Preparation 210b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 0.29-0.34 (2H, m), 0.53-0.60 (2H, m), 1.16-1.24 (1H, m), 1.77-2.01 (2H, m), 2.96-3.05 (1H, m), 3.13 (3H, s), 3.39-3.47 (1H, m), 3.58-3.65 (1H, m), 3.79 (2H, d, J=6.9 Hz), 4.03-4.19 (2H, m), 6.09 (1H, d, J=2.4 Hz), 6.25 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.91 (2H, d, J=9.0 Hz), 7.03 (2H, d, J=9.0 Hz), 7.07 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=5.1 Hz), 7.83 (1H, d, J=5.1 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₇H₂₉N₃O₄, 460; Found, 460.

Preparation 212a: 1-nitro-4-propoxybenzene

The title compound was prepared in 98% yield according to the procedure for Preparation 211a. [M+H] Calc'd for C₉H₁₁NO₃, 182; Found, 182.

Preparation 212b: 4-propoxyaniline

The title compound was prepared in 100% yield from Preparation 212a according to the procedure for Preparation 211b. [M+H] Calc'd for C₉H₁₃NO, 152; Found, 152.

Preparation 212c: N-methyl-4-propoxyaniline

The title compound was prepared in 86% overall yield from 4-propoxyaniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₁₀H₁₅NO, 166; Found, 166.

Preparation 212d: methyl 3-({[(4R)-7-[methyl(4-propoxyphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 56% yield from Preparation 126b and Preparation 212c according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₈H₃₁N₃O₄, 462; Found, 462.

Example 212: 3-({[(4R)-7-[methyl(4-propoxyphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 88% yield from Preparation 212d according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 0.95 (3H, t, J=7.5 Hz), 1.68-1.96 (4H, m), 2.99-3.03 (1H, m), 3.12 (3H, s), 3.40-3.47 (1H, m), 3.59-3.65 (1H, m), 3.90 (2H, t, J=6.3 Hz), 4.09-4.14 (2H, m), 6.10 (1H, s), 6.25 (1H, dd, J=8.4 Hz, 1.5 Hz), 6.89-6.92 (2H, m), 7.02-7.08 (3H, m), 7.59 (1H, d, J=5.1 Hz), 7.84 (1H, d, J=4.8 Hz), 8.39 (1H, s). [M+H] Calc'd for C₂₆H₂₉N₃O₄, 448; Found, 448.

Preparation 213a: 4-cyclopropoxy-N-methylaniline

The title compound was prepared in 17% yield from 1-bromo-4-cyclopropoxybenzene according to the procedure for Preparation 187a. [M+H] Calc'd for C₁₀H₁₃NO, 164; Found, 164.

Preparation 213b: methyl 3-({[(4R)-7-[(4-cyclopropoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 22% yield from Preparation 126b and Preparation 213a according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₂₉N₃O₄, 460; Found, 460.

Example 213: 3-({[(4R)-7-[(4-cyclopropoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 59% yield from Preparation 213b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 0.62-0.68 (2H, m), 0.73-0.80 (2H, m), 1.77-2.01 (2H, m), 2.96-3.05 (1H, m), 3.14 (3H, s), 3.39-3.47 (1H, m), 3.59-3.65 (1H, m), 3.78-3.85 (1H, m), 4.04-4.19 (2H, m), 6.11 (1H, d, J=1.5 Hz), 6.31 (1H, dd, J=8.4 Hz, 1.5 Hz), 7.01-7.10 (5H, m), 7.56 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=4.8 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₆H₂₇N₃O₄, 446; Found, 446.

Preparation 214a: N-methyl-4-(2,2,2-trifluoroethoxy)aniline

The title compound was prepared in 98% overall yield from 4-(2,2,2-trifluoroethoxy)aniline according to the general procedure outlined for Preparation 127a. [M+H] Calc'd for C₉H₁₀F₃NO, 206; Found, 206.

Preparation 214b: methyl 3-({[(4R)-7-{methyl[4-(2,2,2-trifluoroethoxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 35% yield from Preparation 126b and Preparation 214a according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₆H₂₆F₃N₃O₄, 502; Found, 502.

Example 214: 3-({[(4R)-7-{methyl[4-(2,2,2-trifluoroethoxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 62% yield from Preparation 214b according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 1.78-2.03 (2H, m), 2.98-3.07 (1H, m), 3.15 (3H, s), 3.41-3.49 (1H, m), 3.60-3.67 (1H, m), 4.05-4.20 (2H, m), 4.73 (2H, q, J=9.0 Hz), 6.17 (1H, d, J=2.1 Hz), 6.31 (1H, dd, J=8.4 Hz, 2.1 Hz), 7.01-7.12 (5H, m), 7.56 (1H, d, J=4.8 Hz), 7.84 (1H, d, J=4.8 Hz), 8.39 (1H, s). [M+H] Calc'd for C₂₅H₂₄F₃N₃O₄, 488; Found, 488.

Preparation 215a: cyclopropyl(4-(methylamino)phenyl)methanone

The title compound was prepared in 57% yield from 4-bromophenyl cyclopropyl ketone according to the procedure for Preparation 187a. [M+H] Calc'd for C₁₁H₁₃NO, 176; Found, 176.

Preparation 215b: 4-(cyclopropylmethyl)-N-methylaniline

Preparation 215a (0.5 g, 2.85 mmol), hydrazine monohydrate (0.3 ml) and potassium hydroxide (0.4 g) were added to ethylene glycol (5 ml), and the mixture was heated to reflux for 1 h. The hydrazine monohydrate and water were then boiled off by heating open for 2 h. The reaction mixture was cooled and partitioned between water (20 ml) and ethyl acetate (30 ml), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (30 ml) and the combined organic phases were washed with water (15 ml) and brine (15 ml), dried (Na₂SO₄), and concentrated. The residue was purified by silica gel chromatography (0-10% EtOAc/PE) to give 0.22 g (48%) of the title compound as a colorless oil. [M+H] Calc'd for C₁₁H₁₅N, 162; Found, 162.

Preparation 215c: methyl 3-({[(4R)-7-{[4-(cyclopropylmethyl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 40% yield from Preparation 126b and Preparation 215b according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₈H₃₁N₃O₃, 458; Found, 458.

Example 215: 3-({[(4R)-7-{[4-(cyclopropylmethyl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 85% yield from Preparation 215c according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 0.15-0.21 (2H, m), 0.43-0.50 (2H, m), 0.90-1.01 (1H, m), 1.80-1.90 (1H, m), 1.91-2.03 (1H, m), 2.45 (2H, d, J=7.2 Hz), 3.01-3.07 (1H, m), 3.18 (3H, s), 3.41-3.50 (1H, m), 3.61-3.68 (1H, m), 4.06-4.21 (2H, m), 6.26 (1H, d, J=2.1 Hz), 6.41 (1H, dd, J=8.4 Hz, 2.1 Hz), 6.97 (2H, d, J=7.8 Hz), 7.14 (1H, d, J=8.4 Hz), 7.19 (2H, d, J=8.7 Hz), 7.56 (1H, d, J=4.8 Hz), 7.56 (1H, d, J=4.8 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₇H₂₉N₃O₃, 444; Found, 444.

Preparation 216a: methyl 3-({[(4R)-7-[(4-cyclopropanecarbonylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 58% yield from Preparation 126b and Preparation 215a according to the general procedure outlined for Preparation 126c. [M+H] Calc'd for C₂₈H₂₉N₃O₄, 472; Found, 472.

Example 216: 3-({[(4R)-7-[(4-cyclopropanecarbonylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 92% yield from Preparation 215c according to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 0.92-0.95 (4H, m), 1.88-2.07 (2H, m), 2.72-2.82 (1H, m), 3.11-3.20 (1H, m), 3.30 (3H, s), 3.49-3.57 (1H, m), 3.70-3.76 (1H, m), 4.15-4.27 (2H, m), 6.67 (1H, s), 6.75 (1H, d, J=7.5 Hz), 6.81 (2H, d, J=8.4 Hz), 7.38 (1H, d, J=8.4 Hz), 7.58 (1H, d, J=4.8 Hz), 7.85 (1H, d, J=4.8 Hz), 7.89 (2H, d, J=8.4 Hz), 8.41 (1H, s). [M+H] Calc'd for C₂₇H₂₇N₃O₄, 458; Found, 458.

Preparation 217a: (6-bromo-1H-inden-3-yl)methanamine, Hydrochloride

To a solution of 5-bromo-1-indanone (10.0 g, 47.4 mmol) and ZnI₂ (100 mg) in toluene (100 mL) was added TMSCN (15.0 mL, 94.8 mmol) at rt. The solution was heated at 60° C. overnight. The reaction was cooled to rt, and THF (50 mL) was added. LAH (40.0 mL, 2.4 M, 94.8 mmol) was added dropwise at rt, and the reaction was heated at 40° C. for 3 h. EtOAc (50 mL) was added at rt, the reaction mixture was stirred for 30 min. Water (10 mL) was added, and the reaction stirred for 30 min and then was dried (Na₂SO₄), filtered, and concentrated in vacuo to a brown oil.

To a solution of this brown oil in toluene (50 mL) was added HCl/dioxane (30 mL, 1.0 M), and the reaction was stirred at reflux for 10 min. The reaction was cooled to rt, and the solid was collected by filtration to give 8.6 g (70%) of the crude title compound as a yellow solid. [M+H] Calc'd for C₁₀H₁₀BrN, 224, 226; Found, 224, 226.

Preparation 217b: (5-bromo-2,3-dihydro-1H-inden-1-yl)methanamine

To a solution of Preparation 217a (3.0 g, 11.5 mmol) in MeOH (50 mL) and AcOH (5 mL) was added Raney Ni (300 mg) at rt. The mixture was stirred at 50° C. overnight under 50 psi of H₂. After filtration, the solvent was removed under vacuum. The residue was diluted with EtOAc and basified to pH 8 with K₂CO₃. The organic layer was separated, washed with brine, dried (Na₂SO₄) and concentrated to give 2.2 g (85%) of the title compound as a brown oil. [M+H] Calc'd for C₁₀H₁₂BrN, 226, 228; Found, 226, 228.

Preparation 217c: methyl 3-{[(5-bromo-2,3-dihydro-1H-inden-1-yl)methyl]amino}pyridine-4-carboxylate

To a suspension of Preparation 217b (500 mg, 2.2 mmol), methyl 3-bromoisonicotinate (717 mg, 3.3 mmol), Xantphos (192 mg, 0.3 mmol) and Cs₂CO₃ (1.0 g, 3.1 mmol) in toluene (30 mL) was added Pd₂dba₃ (102 mg, 0.1 mmol) at rt under N₂. The reaction was stirred at reflux overnight. After filtration, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography (PE:EtOAc=5:1) to give 380 mg (48%) of the title compound as a yellow oil. [M+H] Calc'd for C₁₇H₁₇BrN₂O₂, 360, 362; Found, 360, 362.

Preparation 217d: methyl 3-({[(1S)-5-[methyl(phenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 217e: methyl 3-({[(1R)-5-[methyl(phenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

To a suspension of Preparation 217c (380 mg, 1.05 mmol), N-methyl aniline (135 mg, 1.26 mmol), Xantphos (91 mg, 0.16 mmol) and Cs₂CO₃ (479 mg, 1.47 mmol) in toluene (30 mL) was added Pd₂dba₃ (48 mg, 0.053 mmol) at rt under N₂. The reaction was stirred at reflux overnight. After filtration, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography (PE:EtOAc=5:1) to give 150 mg (37%) of the product racemate as a yellow oil. [M+H] Calc'd for C₂₄H₂₅N₃O₂, 388; Found, 388.

Separation by chiral prep-HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=80:20, F: 1.0 mL/min, W: 230 nm, T: ambient) gave 60 mg (40%) of Preparation 217d (10.726 min) and 50 mg (33%) of Preparation 217e (13.051 min), each as a yellow oil.

Example 217: 3-({[(1S)-5-[methyl(phenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic Acid

To a solution of Preparation 217d (40 mg, 0.10 mmol) in THF (5 mL) and H₂O (5 mL) was added LiOH.H₂O (4 mg, 0.20 mmol) at rt, and the reaction was stirred for 2 h. THF was removed in vacuo, the residue was acidified to pH=5 with 1.0 N aqueous HCl solution. The precipitate was collected by filtration to give 30 mg (77%) of the title compound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 1.79-1.86 (1H, m), 2.22-2.28 (1H, m), 2.74-2.82 (1H, m), 2.87-2.94 (1H, m), 3.20 (3H, s), 3.27-3.42 (2H, m), 3.59-3.62 (1H, m), 6.81-6.92 (5H, m), 7.17-7.27 (3H, m), 7.54 (1H, d, J=4.8 Hz), 7.81 (1H, d, J=5.1 Hz), 8.32 (1H, s). [M+H] Calc'd for C₂₃H₂₃N₃O₂, 374; Found, 374.

Example 218: 3-({[(1R)-5-[methyl(phenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 90% yield from Preparation 217e according to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ 1.79-1.86 (1H, m), 2.22-2.28 (1H, m), 2.74-2.82 (1H, m), 2.87-2.94 (1H, m), 3.20 (3H, s), 3.27-3.42 (2H, m), 3.59-3.62 (1H, m), 6.81-6.92 (5H, m), 7.17-7.27 (3H, m), 7.54 (1H, d, J=4.8 Hz), 7.81 (1H, d, J=5.1 Hz), 8.32 (1H, s). [M+H] Calc'd for C₂₃H₂₃N₃O₂, 374; Found, 374.

Preparation 219a: methyl 3-({[(1S)-5-[methyl(4-methylphenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 219b: methyl 3-({[(1R)-5-[methyl(4-methylphenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 42% yield from Preparation 217c and N-methyl-p-toluidine according to the procedure for Preparation 217d and 217e. [M+H] Calc'd for C₂₅H₂₇N₃O₂, 402; Found, 402.

Separation by chiral prep-HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=60:40, F: 1.0 mL/min, W: 230 nm, T: ambient) gave Preparation 219a (6.536 min, 43% yield) and Preparation 219b (7.378 min, 40% yield), each as a yellow oil.

Example 219: 3-({[(1S)-5-[methyl(4-methylphenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 89% yield from Preparation 219b according to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ 1.77-1.83 (1H, m), 2.16-2.28 (4H, m), 2.69-2.93 (2H, m), 3.16 (3H, s), 3.29-3.39 (2H, m), 3.57-3.59 (1H, m), 6.70-6.73 (1H, m), 6.80-6.87 (3H, m), 7.05 (2H, d, J=8.1 Hz), 7.20 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=5.1 Hz), 7.81 (1H, d, J=5.1 Hz), 8.32 (1H, s). [M+H] Calc'd for C₂₄H₂₅N₃O₂, 388; Found, 388.

Example 220: 3-({[(1R)-5-[methyl(4-methylphenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 75% yield from Preparation 219a according to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ 1.77-1.83 (1H, m), 2.16-2.28 (4H, m), 2.69-2.93 (2H, m), 3.16 (3H, s), 3.29-3.39 (2H, m), 3.57-3.59 (1H, m), 6.70-6.73 (1H, m), 6.80-6.87 (3H, m), 7.05 (2H, d, J=8.1 Hz), 7.20 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=5.1 Hz), 7.81 (1H, d, J=5.1 Hz), 8.32 (1H, s). [M+H] Calc'd for C₂₄H₂₅N₃O₂, 388; Found, 388.

Preparation 221a: methyl 3-({[(1S)-5-{[4-(dimethylamino)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 221b: methyl 3-({[(1R)-5-{[4-(dimethylamino)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 34% yield from Preparation 217c and 1-N,1-N,4-N-trimethylbenzene-1,4-diamine according to the procedure for Preparation 217d and 217e. [M+H] Calc'd for C₂₆H₃₀N₄O₂, 431; Found, 431.

Separation by chiral prep-HPLC (Column: Chiralcel: ID 5 um 4.6*250 mm, Mobile phase: Hex:IPA=50:50, W: 230 nm, T: 30° C.) gave Preparation 221a (10.573 min, 40% yield) and Preparation 221b (13.379 min, 42% yield), each as a yellow oil.

Example 221: 3-({[(1S)-5-{[4-(dimethylamino)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 77% yield from Preparation 221a according to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ 1.74-1.80 (1H, m), 2.16-2.22 (1H, m), 2.65-3.31 (13H, m), 3.49-3.51 (1H, m), 6.46-7.14 (7H, m), 7.53 (1H, d, J=4.8 Hz), 7.80 (1H, d, J=4.8 Hz), 8.29 (1H, s). [M+H] Calc'd for C₂₅H₂₆N₄O₂, 417; Found, 417.

Example 222: 3-({[(1R)-5-{[4-(dimethylamino)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 78% yield from Preparation 221b according to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ 1.74-1.80 (1H, m), 2.16-2.22 (1H, m), 2.65-3.31 (13H, m), 3.49-3.51 (1H, m), 6.46-7.14 (7H, m), 7.53 (1H, d, J=4.8 Hz), 7.80 (1H, d, J=4.8 Hz), 8.29 (1H, s). [M+H] Calc'd for C₂₅H₂₆N₄O₂, 417; Found, 417.

Preparation 223a: methyl 3-({[(1S)-5-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 223b: methyl 3-({[(1R)-5-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 41% yield from Preparation 217c and 4-cyclopropyl-N-methylaniline according to the procedure for Preparation 217d and 217e. [M+H] Calc'd for C₂₇H₂₉N₃O₂, 428; Found, 428.

Separation by chiral HPLC (Column: Chiralcel: ID 5 um 4.6*250 mm, Mobile phase: Hex:IPA=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave Preparation 223a (9.737 min, 32% yield) and Preparation 223b (11.171 min, 29% yield), each as a yellow oil.

Example 223: 3-({[(1S)-5-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 78% yield from Preparation 223a according to the procedure for Example 217. ¹H NMR (400 MHz, DMSO-d₆): δ 0.52-0.61 (2H, m), 0.86-0.91 (2H, m), 1.23 (1H, s), 1.81-1.87 (2H, m), 2.22-2.25 (1H, m), 2.76-2.78 (1H, m), 2.86-2.90 (1H, m), 3.18 (3H, s), 3.32-3.40 (1H, m), 3.58-3.62 (1H, m), 6.73 (1H, d, J=6.3 Hz), 6.82-6.88 (3H, m), 6.97-6.99 (2H, m), 7.21 (1H, d, J=6.0 Hz), 7.56 (1H, d, J=3.6 Hz), 7.84 (1H, d, J=3.9 Hz), 8.34 (1H, s).

[M+H] Calc'd for C₂₆H₂₇N₃O₂, 414; Found, 414.

Example 224: 3-({[(1R)-5-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 91% yield from Preparation 223b according to the procedure for Example 217. ¹H NMR (400 MHz, DMSO-d₆): δ 0.52-0.61 (2H, m), 0.86-0.91 (2H, m), 1.23 (1H, s), 1.81-1.87 (2H, m), 2.22-2.25 (1H, m), 2.76-2.78 (1H, m), 2.86-2.90 (1H, m), 3.18 (3H, s), 3.32-3.40 (1H, m), 3.58-3.62 (1H, m), 6.73 (1H, d, J=6.3 Hz), 6.82-6.88 (3H, m), 6.97-6.99 (2H, m), 7.21 (1H, d, J=6.0 Hz), 7.56 (1H, d, J=3.6 Hz), 7.84 (1H, d, J=3.9 Hz), 8.34 (1H, s). [M+H] Calc'd for C₂₆H₂₇N₃O₂, 414; Found, 414.

Preparation 225a: 1,3-dimethyl 2-(4-bromo-2-nitrophenyl)propanedioate

To a solution of dimethyl malonate (7.8 mL, 68.2 mmol) in DME (100 mL) at 0° C. was added K₂CO₃ (12.6 g, 91.0 mmol). The reaction mixture was stirred for 30 min, and then 4-bromo-1-fluoro-2-nitrobenzene (10.0 g, 45.5 mmol) was added. The reaction mixture stirred at 40° C. overnight. The reaction was cooled, diluted with water (200 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried (Na₂SO₄) and concentrated. The residue was triturated with PE:EtOAc=8:1 (30 mL) to 13.0 g (86%) of the title compound as a yellow solid. [M+H] Calc'd for C₁₁H₁₀BrNO₆, 332, 334; Found, 332, 334.

Preparation 225b: 2-(4-bromo-2-nitrophenyl)propane-1,3-diol

To a solution of Preparation 225a (500 mg, 1.5 mmol) in dioxane (20 mL) was added BH₃-Me₂S (2.3 mL, 1.0 M in THF, 2.3 mmol) at rt. The reaction was stirred at 70° C. overnight. The reaction was cooled, diluted with water (20 mL), basified to pH 5 with sat. Na₂CO₃, and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried (Na₂SO₄), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=3:2) to give 200 mg (48%) of the title compound as a yellow solid. [M+H] Calc'd for C₉H₁₀BrNO₄, 276, 278; Found, 276, 278.

Preparation 225c: 2-(2-amino-4-bromophenyl)propane-1,3-diol

To a suspension of Preparation 225b (100 mg, 0.36 mmol) and NH₄Cl (10 mg, 0.18 mmol) in dioxane (20 mL) was added Fe (203 mg, 3.60 mmol) at rt. The reaction was stirred at 80° C. for 2 h. The reaction was filtered through Celite. The filtrate was diluted with EtOAc (50 mL), washed with water (50 mL) and brine (50 mL), dried (Na₂SO₄), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=1:1) to give 80 mg (90%) of the title compound as a yellow solid. [M+H] Calc'd for C₉H₁₂BrNO₂, 246, 248; Found, 246, 248.

Preparation 225d: (6-bromo-2,3-dihydro-1-benzofuran-3-yl)methanol

To a solution of Preparation 225c (200 mg, 0.81 mmol) in water (4 mL) and conc. H₂SO₄ (1 mL) was added a solution of NaNO₂ (61 mg, 0.89 mmol) in water (2 mL) at 0° C. The reaction was stirred at rt for 1.5 h, and at 50° C. for 10 min. The reaction was diluted with EtOAc (20 mL), basified to pH 5 with sat. Na₂CO₃, and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (50 mL), dried (Na₂SO₄), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=3:2) to give 81 mg (44%) of the title compound as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 3.56-3.61 (1H, m), 3.78 (2H, dd, J=0.9, 5.7 Hz), 4.47-4.52 (1H, m), 4.66 (1H, t, J=9.0 Hz), 6.95-7.01 (2H, m), 7.07 (1H, d, J=8.1 Hz).

Preparation 225e: (6-bromo-2,3-dihydro-1-benzofuran-3-yl)methyl methanesulfonate

To a solution of Preparation 225d (520 mg, 2.3 mmol) in pyridine (0.5 mL) and DCM (20 mL) was added MsCl (0.2 mL, 2.7 mmol) at 0° C. The reaction was stirred at rt overnight. The reaction was diluted with water (30 mL), and extracted with DCM (30 mL×3). The combined organic layers were washed with 0.1N HCl (10 mL×2) and brine (50 mL), dried (Na₂SO₄), and concentrated to give 650 mg (93%) of the crude title compound as a yellow solid.

Preparation 225f: 3-(azidomethyl)-6-bromo-2,3-dihydro-1-benzofuran

To a solution of Preparation 225e (200 mg, 0.65 mmol) in DMF (10 mL) was added NaN₃ (47 mg, 0.72 mmol) at rt. The reaction was stirred at 55° C. overnight. The solution was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (50 mL), dried (Na₂SO₄) and concentrated. The residue was purified by silica gel chromatography (PE:EA=10:1) to give 107 mg (65%) of the title compound as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 3.44-3.63 (3H, m), 4.37-4.42 (1H, m), 4.65 (1H, t, J=9.0 Hz), 6.97-7.03 (2H, m), 7.08 (1H, d, J=7.8 Hz).

Preparation 225g: (6-bromo-2,3-dihydro-1-benzofuran-3-yl)methanamine

To a solution of Preparation 225f (70 mg, 0.28 mmol) in THF (10 mL) and water (0.5 mL) was added PPh₃ (110 mg, 0.42 mmol) at rt, and the reaction was stirred overnight. The reaction was diluted with water (30 mL), acidified to pH=3 with 1N HCl, and washed with EtOAc (30 mL×2). The aqueous layer was basified to pH=9 with sat. Na₂CO₃ and extracted with EtOAc (30 mL×3). The combined organic layers were dried (Na₂SO₄) and concentrated to give 50 mg (78%) of the title compound as a yellow oil. [M+H] Calc'd for C₉H₁₀BrNO, 228, 230; Found, 228, 230.

Preparation 225h: methyl 3-{[(6-bromo-2,3-dihydro-1-benzofuran-3-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 63% yield from Preparation 225g according to the procedure for Preparation 217c. [M+H] Calc'd for C₁₆H₁₅BrN₂O₃, 363; Found, 363.

Preparation 225j: methyl 3-({[(3S)-6-[methyl(4-methylphenyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 225k: methyl 3-({[(3R)-6-[methyl(4-methylphenyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 60% yield from Preparation 225h and N-methyl-p-toluidine according to the procedure for Preparation 217d and 217e. [M+H] Calc'd for C₂₄H₂₅N₃O₃, 404; Found, 404.

Separation by chiral prep-HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=50:50, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave Preparation 225j (7.814 min, 33% yield) and Preparation 225k (10.720 min, 38% yield), each as a yellow oil.

Example 225: 3-({[(3S)-6-[methyl(4-methylphenyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 97% yield from Preparation 225j according to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ 2.24 (3H, s), 3.15 (3H, s), 3.47 (2H, d, J=6.9 Hz), 3.67-3.71 (1H, m), 4.29-4.34 (1H, m), 4.57 (1H, t, J=8.7 Hz), 6.27-6.34 (2H, m), 6.92 (2H, d, J=8.1 Hz), 7.08-7.14 (3H, m), 7.54 (1H, d, J=5.4 Hz), 7.83 (1H, d, J=5.1 Hz), 8.33 (1H, s). [M+H] Calc'd for C₂₃H₂₃N₃O₃, 390; Found, 390.

Example 226: 3-({[(3R)-6-[methyl(4-methylphenyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 98% yield from Preparation 225k according to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ 2.24 (3H, s), 3.15 (3H, s), 3.47 (2H, d, J=6.9 Hz), 3.67-3.71 (1H, m), 4.29-4.34 (1H, m), 4.57 (1H, t, J=8.7 Hz), 6.27-6.34 (2H, m), 6.92 (2H, d, J=8.1 Hz), 7.08-7.14 (3H, m), 7.54 (1H, d, J=5.4 Hz), 7.83 (1H, d, J=5.1 Hz), 8.33 (1H, s). [M+H] Calc'd for C₂₃H₂₃N₃O₃, 390; Found, 390.

Preparation 227a: methyl 3-({[(3S)-6-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 227b: methyl 3-({[(3R)-6-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 70% yield from Preparation 225h and 4-cyclopropyl-N-methylaniline according to the procedure for Preparation 217d and 217e. [M+H] Calc'd for C₂₄H₂₅N₃O₃, 404; Found, 404. [M+H] Calc'd for C₂₆H₂₇N₃O₃, 430; Found, 430.

Separation by chiral prep-HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=50:50, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave Preparation 227a (8.246 min, 17% yield) and Preparation 227b (11.339 min, 19% yield), each as a yellow oil.

Example 227: 3-({[(3S)-6-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 98% yield from Preparation 227a according to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ 0.57-0.62 (2H, m), 0.85-0.91 (2H, m), 1.82-1.87 (1H, m), 3.14 (3H, s), 3.48 (2H, d, J=6.3 Hz), 3.67-3.71 (1H, m), 4.29-4.34 (1H, m), 4.57 (1H, t, J=9.0 Hz), 6.26-6.33 (2H, m), 6.91 (2H, d, J=8.7 Hz), 6.98 (2H, d, J=8.7 Hz), 7.12 (1H, d, J=7.8 Hz), 7.54 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=4.8 Hz), 8.35 (1H, s).

[M+H] Calc'd for C₂₅H₂₅N₃O₃, 416; Found, 416.

Example 228: 3-({[(3R)-6-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 94% yield from Preparation 227b according to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ 0.57-0.62 (2H, m), 0.85-0.91 (2H, m), 1.82-1.87 (1H, m), 3.14 (3H, s), 3.48 (2H, d, J=6.3 Hz), 3.67-3.71 (1H, m), 4.29-4.34 (1H, m), 4.57 (1H, t, J=9.0 Hz), 6.26-6.33 (2H, m), 6.91 (2H, d, J=8.7 Hz), 6.98 (2H, d, J=8.7 Hz), 7.12 (1H, d, J=7.8 Hz), 7.54 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=4.8 Hz), 8.35 (1H, s). [M+H] Calc'd for C₂₅H₂₅N₃O₃, 416; Found, 416.

Preparation 229a: 4-bromo-2-(chloromethyl)-1-iodobenzene

To a solution of (5-bromo-2-iodophenyl)methanol (1.4 g, 4.5 mmol) in DCM (20 mL) was added SOCl₂ (3.2 g, 26.9 mmol) at 0° C., and the reaction was stirred at rt overnight. The solution was concentrated, and the residue was purified silica gel chromatography (PE) to give 1.2 g (81%) of the title compound as a brown solid.

Preparation 229b: [(5-bromo-1,3-dihydro-2-benzofuran-1-yl)methoxy](tert-butyl)dimethylsilane

To a solution of Preparation 229a (1.0 g, 3.0 mmol) in THF (25 mL) was added i-PrMgBr (1.6 mL, 2.0 M in THF, 3.2 mmol) at −10° C., and the mixture was stirred for 2 min. (tert-Butyl-dimethylsiloxy)acetaldehyde (578 g, 3.3 mmol) was added at −10° C. The reaction mixture was stirred at rt for 1 h, and then was heated at reflux overnight. The reaction was cooled, diluted with water (30 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried (Na₂SO₄), and concentrated. The residue was purified by silica gel chromatography (PE) to give 680 mg (66%) of the title compound as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 0.02 (3H, s), 0.04 (3H, s), 0.86 (9H, s), 3.72-3.78 (1H, m), 3.82-3.87 (1H, m), 5.02-5.18 (3H, m), 7.15 (1H, d, J=8.1 Hz), 7.35-7.39 (2H, m). [M+H] Calc'd for C₁₅H₂₃BrO₂Si, 343, 345; Found, 343, 345.

Preparation 229c: (5-bromo-1,3-dihydro-2-benzofuran-1-yl)methanol

To a solution of Preparation 229b (5.0 g, 14.6 mmol) in THF (100 mL) was added TBAF (27.4 mL, 1.0 M in THF, 24.7 mmol) at rt, and the reaction was stirred for 30 min. The reaction was diluted with water (100 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried (Na₂SO₄), and concentrated to give 3.0 g (90%) of the title compound as a white solid. [M+H] Calc'd for C₉H₉BrO₂, 229, 231; Found, 229, 231.

Preparation 229d: (5-bromo-1,3-dihydro-2-benzofuran-1-yl)methyl methanesulfonate

To a solution of Preparation 229c (5.0 g, 13.2 mmol) in pyridine (3 mL) and DCM (100 mL) was added MsCl (1.2 mL, 15.8 mmol) at 0° C., and the reaction was stirred at rt overnight. The solution was diluted with water (100 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with 0.1 N HCl (20 mL×2) and brine (50 mL), dried (Na₂SO₄), and concentrated to give 4.0 g (100%) of the title compound as a colorless oil.

Preparation 229e: 1-(azidomethyl)-5-bromo-1,3-dihydro-2-benzofuran

To a solution of Preparation 229d (4.0 g, 13.1 mmol) in DMF (50 mL) was added NaN₃ (898 mg, 13.8 mmol) at rt, and the reaction was stirred at 60° C. overnight. The reaction was diluted with water (100 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine (100 mL), dried (Na₂SO₄), and concentrated. The residue was purified by silica gel chromatography (PE:EA=10:1) to give 1.9 g (57%) of the title compound as a yellow oil.

Preparation 229f: (5-bromo-1,3-dihydro-2-benzofuran-1-yl)methanamine

To a solution of Preparation 229e (1.9 g, 7.5 mmol) in THF (50 mL) and water (8 mL) was added PPh₃ (3.0 g, 11.3 mmol) at rt, and the reaction was stirred at 60° C. overnight. The reaction was diluted with water (50 mL), acidified to pH=3 with 1N HCl, and washed with EtOAc (50 mL×2). The aqueous layer was basified to pH=9 with sat. Na₂CO₃ and extracted with EtOAc (50 mL×3). The combined organic layers were dried (Na₂SO₄) concentrated to give 1.0 g (59%) of the title compound as a yellow oil. [M+H] Calc'd for C₉H₁₀BrNO, 228, 230; Found, 228, 230.

Preparation 229g: methyl 3-{[(5-bromo-1,3-dihydro-2-benzofuran-1-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 53% yield from Preparation 229f according to the procedure for Preparation 217c. [M+H] Calc'd for C₁₆H₁₅BrN₂O₃, 363, 365; Found, 363, 365.

Preparation 229h: methyl 3-({[(1S)-5-[methyl(4-methylphenyl)amino]-1,3-dihydro-2-benzofuran-1-yl]methyl}amino)pyridine-4-carboxylate; and Preparation 229j: methyl 3-({[(1S)-5-[methyl(4-methylphenyl)amino]-1,3-dihydro-2-benzofuran-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 75% yield from Preparation 229g and N-methyl-p-toluidine according to the procedure for Preparation 217d and 217e. [M+H] Calc'd for C₂₄H₂₅N₃O₃, 404; Found, 404.

Separation by chiral prep-HPLC (Column: Chiralcel: IE 5 um 4.6*250 mm, Mobile phase: Hex:EtOH=50:50, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave Preparation 229h (9.673 min, 16% yield) and Preparation 229j (11.741 min, 18% yield), each as a yellow oil.

Example 229: 3-({[(1S)-5-[methyl(4-methylphenyl)amino]-1,3-dihydro-2-benzofuran-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 90% yield from Preparation 229h according to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ 2.26 (3H, s), 3.20 (3H, s), 3.48-3.54 (1H, m), 3.74-3.78 (1H, m), 4.90-4.99 (2H, m), 5.33-5.35 (1H, m), 6.78-6.80 (2H, m), 6.94 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.24 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=5.1 Hz), 7.82 (1H, d, J=5.1 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₃H₂₃N₃O₃, 390; Found, 390.

Example 230: 3-({[(1R)-5-[methyl(4-methylphenyl)amino]-1,3-dihydro-2-benzofuran-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 93% yield from Preparation 229j according to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ 2.26 (3H, s), 3.20 (3H, s), 3.48-3.54 (1H, m), 3.74-3.78 (1H, m), 4.90-4.99 (2H, m), 5.33-5.35 (1H, m), 6.78-6.80 (2H, m), 6.94 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.24 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=5.1 Hz), 7.82 (1H, d, J=5.1 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₃H₂₃N₃O₃, 390; Found, 390.

Preparation 231a: 6-bromo-1H-indene-3-carboxamide

To a solution of 5-bromo-1-indanone (50 g, 0.23 mol) in toluene (2000 mL) was added ZnI₂ (1.5 g), and the mixture was stirred at 40° C. until dissolved. TMSCN (76 mL, 0.57 mol) was added, and the reaction was stirred at reflux for 6 h. The solution was concentrated, and the residue was dissolved in 300 mL HOAc. While keeping the temperature under 25° C., concentrated H₂SO₄ (100 mL) was added, followed by water (30 mL), and then the reaction mixture was heated at 130° C. for 2 h. The solution was cooled to rt, diluted with water, and the solid was collected by filtration. The filter cake was triturated in THF and collected by filtration to give 25 g (44%) of the title compound as yellow solid. [M+H] Calc'd for C₁₀H₈BrNO, 238, 240; Found, 238, 240.

Preparation 231b: (1R)-5-bromo-2,3-dihydro-1H-indene-1-carboxamide

To a solution of Preparation 231a (5.0 g, 21 mmol) in MeOH/THF (200 mL, 1:1) was added Ru(OAc)₂[s-binap] (250 mg). The mixture was stirred overnight at 60° C. under 5.0 M Pa of hydrogen. The mixture was filtered and concentrated to give 5.3 g (100%) of the crude title compound as a brown solid (ee>95%). [M+H] Calc'd for C₁₀H₁₀BrNO, 240, 242; Found, 240, 242. Analytical Column: Chiralcel: AS-H, Mobile phase: Hex:EtOH=60:40.

Preparation 231c: [(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]methanamine

To a solution of Preparation 231b (5.3 g, 22 mmol) in THF (50 mL) was added BH₃-THF (110 mL, 110 mmol, 1.0 M). The resulting mixture was stirred at rt overnight. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated to give 4.27 g (85%) of the title compound as a brown oil. [M+H] Calc'd for C₁₀H₁₂BrN, 226, 228; Found, 226, 228.

Preparation 231d: methyl 3-({[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 231c (4.27 g, 18.9 mmol) in toluene (100 mL) was added methyl 3-bromoisonicotinate (4.9 g, 23 mmol), Cs₂CO₃ (8.6 g, 26 mmol), Xantphos (655 mg, 1.13 mmol) and Pd₂(dba)₃ (348 mg, 0.378 mmol). The mixture was stirred overnight at 120° C. under nitrogen. After filtration and concentration, the residue was purified by silica gel chromatography (PE:EtOAc=2:1) to give 1.8 g (26%) of the title compound as a brown oil. [M+H] Calc'd for C₁₇H₁₇BrN₂O₂, 361, 363; Found, 361, 363.

Preparation 231e: methyl 3-({[(1R)-5-[methyl(3-methylphenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 231d (200 mg, 0.554 mmol) in toluene (15 mL) was added compound N-methyl-m-toluidine (80 mg, 0.66 mmol), Cs₂CO₃ (253 mg, 0.776 mmol), Xantphos (48 mg, 0.083 mmol) and Pd₂(dba)₃ (26 mg, 0.028 mmol). The mixture was stirred overnight at 120° C. under nitrogen. After filtration and concentration, the residue was purified by prep-HPLC to give 62 mg (28%) of the title compound as a yellow oil. [M+H] Calc'd for C₂₅H₂₇N₃O₃, 402; Found, 402.

Example 231: 3-({[(1R)-5-[methyl(3-methylphenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 75% yield from Preparation 231d according to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ 1.79-1.85 (1H, m), 2.21-2.27 (4H, m), 2.72-2.96 (2H, m), 3.15 (3H, s), 3.37-3.41 (2H, m), 3.58-3.62 (1H, m), 6.65-6.72 (3H, m), 6.80 (1H, d, J=8.1 Hz), 6.89 (1H, s), 7.06-7.11 (1H, m), 7.24 (1H, d, J=8.1 Hz), 7.54 (1H, d, J=4.8 Hz), 7.82 (1H, d, J=5.4 Hz), 8.33 (1H, s). [M+H] Calc'd for C₂₄H₂₅N₃O₂, 388; Found, 388.

Preparation 232a: methyl 3-({[(1R)-5-[(4-ethylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 26% yield from Preparation 231d and 4-ethyl-N-methylaniline according to the procedure for Preparation 231e. [M+H] Calc'd for C₂₆H₂₉N₃O₂, 416; Found, 416.

Example 232: 3-({[(1R)-5-[(4-ethylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 77% yield from Preparation 232a according to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ 1.14 (3H, t, J=7.5 Hz), 1.77-1.84 (1H, m), 2.16-2.25 (1H, m), 2.53 (2H, m), 2.72-2.79 (1H, m), 2.84-2.92 (1H, m), 3.17 (3H, s), 3.24-3.30 (2H, m), 3.55-3.60 (1H, m), 6.73 (1H, dd, J=1.5, 8.4 Hz), 6.82-6.88 (3H, m), 7.08 (2H, d, J=8.4 Hz), 7.20 (1H, d, J=7.8 Hz), 7.55 (1H, d, J=5.1 Hz), 7.82 (1H, d, J=5.1 Hz), 8.32 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₂, 402; Found, 402.

Preparation 233a: methyl 3-({[(1R)-5-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 231d and N-methyl-4-(pyrrolidin-1-yl)aniline according to the procedure for Preparation 231e. [M+H] Calc'd for C₂₈H₃₂N₄O₂, 457; Found, 457.

Example 233: 3-({[(1R)-5-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic Acid

The title compound was prepared in 47% yield from Preparation 233a according to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): 1.77 (1H, m), 1.79 (4H, m), 2.20-2.22 (1H, m), 2.70-2.73 (1H, m), 2.82-2.84 (1H, m), 3.13 (3H, s), 3.22 (4H, m), 3.32 (2H, m), 3.47-3.49 (1H, m), 6.48 (4H, m), 6.95-6.97 (2H, d, J=6.0 Hz), 7.09-7.12 (1H, m), 7.55-7.57 (1H, d, J=6.9 Hz), 7.79 (1H, d, J=5.1 Hz), 8.24 (1H, s). [M+H] Calc'd for C₂₇H₃₀N₄O₂, 442; Found, 443.

II. Biological Evaluation Example 1a: In Vitro Enzyme Inhibition Assay for JMJD2C Activity

This assay determines the ability of a test compound to inhibit JMJD2C demethylase activity. Baculovirus expressed JMJD2C (GenBank Accession #BC143571, AA 2-372) was purchased from BPS Bioscience (Cat#50105).

JMJD2C Assay

The ability of test compounds to inhibit the activity of JMJD2C was determined in 384-well plate format under the following reaction conditions: 0.3 nM JMJD2C, 300 nM H3K9me3-biotin labeled peptide (Anaspec cat #64360), 2 μM alpha-ketoglutaric acid in assay buffer of 50 mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodium L-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product was determined quantitatively by TR-FRET after the addition of detection reagent Phycolink Streptavidin-allophycocyanin (Prozyme) and Europium-anti-di-methylated histone H3 lysine 9 (H3K9me2) antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer (PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.

The assay reaction was initiated by the following: 2 μl of the mixture of 900 nM H3K9me3-biotin labeled peptide and 6 μM alpha-ketoglutaric acid with 2 μl of 11-point serial diluted inhibitor in 3% DMSO were added to each well of the plate, followed by the addition of 2 μl of 0.9 nM JMJD2C to initiate the reaction. The reaction mixture was incubated at room temperature for 30 minutes, and terminated by the addition of 6 μl of 5 mM EDTA in LANCE detection buffer containing 100 nM Phycolink Streptavidin-allophycocyanin and 2 nM Europium-anti-H3K9me2 antibody. Plates were read by EnVisionMultilabel Reader in TR-FRET mode (excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hour incubation at room temperature. A ratio was calculated (665/615) for each well and fitted to determine inhibition constant (IC₅₀).

Example 1b: In Vitro Enzyme Inhibition Assay for JMJD3 Activity

This assay determines the ability of a test compound to inhibit JMJD3 demethylase activity. Baculovirus expressed JMJD3 (GenBank Accession #NM-001080424, AA1043-end) was purchased from BPS Bioscience (Cat#50115).

JMJD3 Assay

The enzymatic assay of JMJD3 activity is based upon Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) detection. The ability of test compounds to inhibit the activity of JMJD3 was determined in 384-well plate format under the following reaction conditions: 5 nM JMJD3, 250 nM H3K27me3-biotin labeled peptide (Anaspec cat #64367), 0.4 to 2 μM alpha-ketoglutaric acid in assay buffer of 50 mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodium L-ascorbate, and 5 μM ammonium iron(II) sulfate. Reaction product was determined quantitatively by TR-FRET after the addition of detection reagent Phycolink Streptavidin-allophycocyanin (Prozyme) and Europium-anti-di-methylated histone H3 lysine 27 (H3K27me2) antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer (PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.

The assay reaction was initiated by the following: 2 μl of the mixture of 750 nM H3K27me3-biotin labeled peptide and 1.2 to 6 μM alpha-ketoglutaric acid with 2 μL of 11-point serial diluted inhibitor in 3% DMSO were added to each well of plate, followed by the addition of 2 μl of 15 nM JMJD3 to initiate the reaction. The reaction mixture was incubated at room temperature for 30 minutes, and terminated by the addition of 6 μL of 5 mM EDTA in LANCE detection buffer containing 100 nM Phycolink Streptavidin-allophycocyanin and 2 nM Europium-anti-H3K27me2 antibody. Plates were read by EnVisionMultilabel Reader in TR-FRET mode (excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hour incubation at room temperature. A ratio from the readout of 665/615 was calculated for each well and fitted to determine inhibition constant (IC₅₀).

The ability of the compounds disclosed herein to inhibit demethylase activity was quantified and the respective IC₅₀ value was determined. Table 3 provides the IC₅₀ values of various compounds disclosed herein.

TABLE 3 Chemical Synthesis JMJD2C JMJD3 Example Name IC₅₀ (nM) IC₅₀ (nM) 1 3-({[(1S)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1- C C yl]methyl}amino)pyridine-4-carboxylic acid 2 3-({[(1S)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1- B C yl]methyl}amino)pyridine-4-carboxylic acid 3 3-({[6-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 4 3-({[6-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 5 3-({[6-(2,3-dihydro-1H-indol-1-yl)-1,2,3,4-tetrahydronaphthalen-1- C yl]methyl}amino)pyridine-4-carboxylic acid 6 3-({[(1R)-6-[(2-fluorophenyl)(methyl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 7 3-({[(1R)-6-[(3-fluorophenyl)(methyl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 8 3-({[(1R)-6-[(4-fluorophenyl)(methyl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 9 3-({[(1R)-6-[(4-chlorophenyl)(methyl)amino]-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 10 3-({[(1R)-6-[ethyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 11 3-({[(1R)-6-[methyl(pyridin-2-yl)amino]-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 12 3-({[(1R)-6-[methyl(pyridin-3-yl)amino]-1,2,3,4- A tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 13 3-({[(1R)-6-[(6-methoxypyridin-3-yl)(methyl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 14 3-{[(7-bromo-3,4-dihydro-2H-1-benzopyran-4- B yl)methyl]amino}pyridine-4-carboxylic acid 15 3-({[7-(phenylamino)-3,4-dihydro-2H-1-benzopyran-4- B yl]methyl}amino)pyridine-4-carboxylic acid 16 3-({[7-(1,2,3,4-tetrahydroquinolin-1-yl)-3,4-dihydro-2H-1- B C benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 17 3-({[7-(2,3-dihydro-1H-indol-1-yl)-3,4-dihydro-2H-1-benzopyran- B C 4-yl]methyl}amino)pyridine-4-carboxylic acid 18 3-({[(4R)-7-[methyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran- B B 4-yl]methyl}amino)pyridine-4-carboxylic acid 19 3-({[(4R)-7-[(2-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 20 3-({[(4R)-7-[(3-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1- B C benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 21 3-({[(4R)-7-[(4-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1- B C benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 22 3-({[(4R)-7-[methyl(4-methylphenyl)amino]-3,4-dihydro-2H-1- B C benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 23 3-({[(4R)-7-[(4-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1- B C benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 24 3-({[(4R)-7-[ethyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4- B C yl]methyl}amino)pyridine-4-carboxylic acid 25 3-{[(2-phenyl-5,6,7,8-tetrahydroquinolin-5- B B yl)methyl]amino}pyridine-4-carboxylic acid 26 3-[({2-[methyl(phenyl)amino]-5,6,7,8-tetrahydroquinolin-5- B C yl}methyl)amino]pyridine-4-carboxylic acid 27 3-[({7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran- C 4-yl}methyl)amino]pyridine-4-carboxylic acid 28 3-({[7-(furan-3-yl)-3,4-dihydro-2H-1-benzopyran-4- B A yl]methyl}amino)pyridine-4-carboxylic acid 29 3-({[(4S)-7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4- C B yl]methyl}amino)pyridine-4-carboxylic acid 30 3-({[(4R)-7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4- B yl]methyl}amino)pyridine-4-carboxylic acid 31 3-({[(4S)-7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4- C B yl]methyl}amino)pyridine-4-carboxylic acid 32 3-({[(4R)-7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4- B yl]methyl}amino)pyridine-4-carboxylic acid 33 3-({[(4S)-7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4- C A yl]methyl}amino)pyridine-4-carboxylic acid 34 3-({[(4R)-7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4- B C yl]methyl}amino)pyridine-4-carboxylic acid 35 3-({[(4R)-7-cyclohexyl-3,4-dihydro-2H-1-benzopyran-4- B yl]methyl}amino)pyridine-4-carboxylic acid 36 3-({[(4S)-7-(2-methylthiophen-3-yl)-3,4-dihydro-2H-1- C B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 37 3-({[(4R)-7-(2-methylthiophen-3-yl)-3,4-dihydro-2H-1- C C benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 38 3-({[7-(3-methylbut-1-yn-1-yl)-3,4-dihydro-2H-1-benzopyran-4- B yl]methyl}amino)pyridine-4-carboxylic acid 39 3-({[(4S)-7-(2-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4- C B yl]methyl}amino)pyridine-4-carboxylic acid 40 3-({[(4R)-7-(2-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4- B C yl]methyl}amino)pyridine-4-carboxylic acid 41 3-({[(4S)-7-(3-fluoro-2-methylphenyl)-3,4-dihydro-2H-1- C benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 42 3-({[(4R)-7-(3-fluoro-2-methylphenyl)-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 43 3-({[(4R)-7-(5-fluoro-2-methylphenyl)-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 44 3-({[(4R)-7-(2-chloro-3-fluorophenyl)-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 45 3-({[(4R)-7-(2-chloro-5-fluorophenyl)-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 46 3-({[(4R)-7-[2-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 47 3-({[(4S)-7-phenoxy-3,4-dihydro-2H-1-benzopyran-4- C yl]methyl}amino)pyridine-4-carboxylic acid 48 3-({[(4R)-7-phenoxy-3,4-dihydro-2H-1-benzopyran-4- B yl]methyl}amino)pyridine-4-carboxylic acid 49 3-({[7-(thiophen-2-ylsulfanyl)-3,4-dihydro-2H-1-benzopyran-4- B yl]methyl}amino)pyridine-4-carboxylic acid 50 3-({[(4S)-7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1- C benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 51 3-({[(4R)-7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 52 3-({[(4S)-7-[(3-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1- C B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 53 3-({[(4R)-7-[(3-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 54 3-({[(4S)-7-[(4-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1- C B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 55 3-({[(4R)-7-[(4-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1- B C benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 56 3-[({6-[(6-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydronaphthalen-1- B yl}methyl)amino]pyridine-4-carboxylic acid 57 3-({[(1S)-6-(2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1- C yl]methyl}amino)pyridine-4-carboxylic acid 58 3-({[(1R)-6-(2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 59 3-{[(6-propoxy-1,2,3,4-tetrahydronaphthalen-1- B yl)methyl]amino}pyridine-4-carboxylic acid 60 3-({[(1S)-6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1- C yl]methyl}amino)pyridine-4-carboxylic acid 61 3-({[(1R)-6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 62 3-[({6-[2-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydronaphthalen- C 1-yl}methyl)amino]pyridine-4-carboxylic acid 63 3-({[6-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 64 3-({[(1R)-6-(4-fluoro-2-methylphenoxy)-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 65 3-({[(1R)-6-(2,4-difluorophenoxy)-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 66 3-({[(1R)-6-(2-fluoro-4-methylphenoxy)-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 67 3-({[(1R)-6-(2-chlorophenoxy)-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 68 3-({[(1S)-6-[(3-methylphenyl)sulfanyl]-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 69 3-({[(1R)-6-[(3-methylphenyl)sulfanyl]-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 70 3-({[(1S)-6-[(2-methylphenyl)sulfanyl]-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 71 3-({[(1R)-6-[(2-methylphenyl)sulfanyl]-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 72 3-({[(1S)-6-[(2-fluorophenyl)sulfanyl]-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 73 3-({[(1R)-6-[(2-fluorophenyl)sulfanyl]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 74 3-({[(1S)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 75 3-({[(1R)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 76 3-({[(1S)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 77 3-({[(1R)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 78 3-({[(1S)-6-[(4-methylphenyl)sulfanyl]-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 79 3-({[(1R)-6-[(4-methylphenyl)sulfanyl]-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 80 3-({[6-(pyridin-2-ylsulfanyl)-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 81 3-({[(1S)-6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 82 3-({[(1R)-6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 83 3-({[(1S)-6-(4-methylbenzenesulfonyl)-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 84 3-({[(1R)-6-(4-methylbenzenesulfonyl)-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 85 3-({[(1S)-6-(3-methylbenzenesulfonyl)-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 86 3-({[(1R)-6-(3-methylbenzenesulfonyl)-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 87 3-({[6-(3-fluorobenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 88 3-({[6-(oxan-4-yl)-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 89 3-({[6-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 90 3-({[(1S)-6-ethyl-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 91 3-({[(1R)-6-ethyl-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 92 3-({2H,3H,6H,7H,8H,9H-naphtho[1,2-b]furan-6- B ylmethyl}amino)pyridine-4-carboxylic acid 93 3-{[(6,7-dimethyl-3,4-dihydro-2H-1-benzopyran-4- B yl)methyl]amino}pyridine-4-carboxylic acid 94 3-{[(6-methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-1- B yl)methyl]amino}pyridine-4-carboxylic acid 95 3-{[(6,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-1- B yl)methyl]amino}pyridine-4-carboxylic acid 96 3-({[(1S)-7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 97 3-({[(1R)-7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 98 3-({[(1S)-6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 99 3-({[(1R)-6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1- B B yl]methyl}amino)pyridine-4-carboxylic acid 100 3-({[(4S)-7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4- C yl]methyl}amino)pyridine-4-carboxylic acid 101 3-({[(4R)-7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4- B yl]methyl}amino)pyridine-4-carboxylic acid 102 3-({[(4R)-7-(5-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 103 3-({[(1R)-6-[(4-cyanophenyl)(methyl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 104 3-({[(4R)-7-[(2,4-difluorophenyl)(methyl)amino]-3,4-dihydro-2H- B 1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 105 3-({[(4R)-7-[methyl(3-methylphenyl)amino]-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 106 3-({[(1R)-6-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1- B yl]methyl}amino)pyridine-4-carboxylic acid 107 3-({[(4R)-7-(2-chloro-5-methoxyphenyl)-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 108 3-({[(1R)-6-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 109 3-({[(4R)-7-[(3,5-difluorophenyl)(methyl)amino]-3,4-dihydro-2H- B 1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 110 3-({[(4R)-7-[(3-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1- C benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 111 3-({[(4R)-7-[methyl(2-methylphenyl)amino]-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 112 3-({[(4R)-7-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-3,4- B dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 113 3-({[(1R)-6-[methyl(oxan-4-yl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 114 3-({[(1R)-6-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 115 3-({[(1R)-6-[(3-cyanophenyl)(methyl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 116 3-({[(4R)-7-(2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4- B yl]methyl}amino)pyridine-4-carboxylic acid 117 3-({[(4R)-7-[(3-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 118 3-({[(4R)-7-(4-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 119 3-({[(4R)-7-[(4-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 120 3-({[(1R)-6-[(cyclopropylmethyl)(methyl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 121 3-({[(1R)-6-[methyl(6-methoxypyridin-2-yl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 122 3-({[(1R)-6-[methyl(5-methylpyridin-2-yl)amino]-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 123 3-({[(1R)-6-[methyl(6-methylpyridin-2-yl)amino]-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 124 3-({[(4R)-7-(2-cyanophenyl)-3,4-dihydro-2H-1-benzopyran-4- B yl]methyl}amino)pyridine-4-carboxylic acid 125 3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-3-yl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 126 3-({[(4R)-7-[(4-ethynylphenyl)(methyl)amino]-3,4-dihydro-2H-1- B C benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 127 3-({[(4R)-7-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]-3,4- B dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 128 3-({[(4R)-7-{methyl[4-(trifluoromethyl)phenyl]amino}-3,4- C dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 129 3-[({7-[phenyl(2,2,2-trifluoroethyl)amino]-3,4-dihydro-2H-1- C benzopyran-4-yl}methyl)amino]pyridine-4-carboxylic acid 130 3-({[(1R)-6-[benzyl(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- B C yl]methyl}amino)pyridine-4-carboxylic acid 131 3-({[(4R)-7-[(2,3-dihydro-1H-inden-5-yl)(methyl)amino]-3,4- B C dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 132 3-({[(1R)-6-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]- B 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid 133 3-({[(1R)-6-[cyclopentyl(methyl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 134 3-({[(4R)-7-[(4-cyclopropylphenyl)(methyl)amino]-3,4-dihydro- B C 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 135 3-({[(1R)-6-[(1-benzofuran-6-yl)(methyl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 136 3-({[(4R)-7-[(1-benzofuran-5-yl)(methyl)amino]-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 137 3-({[(1R)-6-[(1-benzofuran-5-yl)(methyl)amino]-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 138 3-({[(4R)-7-(2-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4- B C yl]methyl}amino)pyridine-4-carboxylic acid 139 3-({[(4R)-7-[methyl(2-methyl-1,3-thiazol-4-yl)amino]-3,4-dihydro- B 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 140 3-({[(1R)-6-[methyl(4-methylphenyl)amino]-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 141 3-({[(4R)-7-[(1-benzofuran-6-yl)(methyl)amino]-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 142 3-[(3,4-dihydro-1H-2-benzopyran-1-ylmethyl)amino]pyridine-4- B carboxylic acid 143 3-({[(1R)-6-[methyl(3-methylphenyl)amino]-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 144 3-({[(1R)-6-[methyl(thiophen-2-yl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 145 3-({[(4R)-7-[methyl(5-methylpyridin-2-yl)amino]-3,4-dihydro-2H- A C 1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 146 3-[({6-[methyl(phenyl)amino]-3,4-dihydro-1H-2-benzopyran-1- B yl}methyl)amino]pyridine-4-carboxylic acid 147 3-({[(1R)-6-[(2-hydroxyethyl)(phenyl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 148 3-({[(4R)-7-[methyl(6-methylpyridin-2-yl)amino]-3,4-dihydro-2H- B 1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 149 3-[(1,2,3,4-tetrahydroisoquinolin-1-ylmethyl)amino]pyridine-4- B carboxylic acid 150 3-({[(1R)-6-[(3-methoxyphenyl)(methyl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 151 3-({[(4R)-7-[(3-fluoro-4-methylphenyl)(methyl)amino]-3,4- B dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 152 3-({[(4R)-7-[(5-chloropyridin-2-yl)(methyl)amino]-3,4-dihydro- B 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 153 3-({[(4R)-7-[(5-cyclopropylpyridin-2-yl)(methyl)amino]-3,4- B C dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 154 3-({[(4R)-7-[(4-ethylphenyl)(methyl)amino]-3,4-dihydro-2H-1- B C benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 155 3-({[(1R)-6-[methyl(1-methyl-2-oxo-1,2-dihydropyridin-4- B yl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 156 3-({[(1R)-6-[methyl(5-methylpyrimidin-2-yl)amino]-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 157 3-({[(4R)-7-[(5-ethylpyridin-2-yl)(methyl)amino]-3,4-dihydro-2H- B C 1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 158 3-({[(1R)-6-{[4-(hydroxymethyl)phenyl](methyl)amino}-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 159 3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-4-yl)amino]-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 160 3-({[(1R)-6-{[4-(dimethylamino)phenyl](methyl)amino}-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 161 3-({[(1R)-6-[(4-cyclopropylphenyl)(methyl)amino]-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 162 3-({[(1R)-6-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 163 3-({[(1R)-6-[(4-cyclopropylphenyl)(2-methoxyethyl)amino]- C 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid 164 3-({[(1R)-6-{[4-(methoxymethyl)phenyl](methyl)amino}-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 165 3-({[(1R)-6-[(4-hydroxyphenyl)(methyl)amino]-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 166 3-({[(1R)-6-[(dimethyl-1,2-oxazol-4-yl)(methyl)amino]-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 167 3-({[(1R)-6-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 168 3-({[(1R)-6-({4-[(1R)-1-hydroxyethyl]phenyl}(methyl)amino)- B 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid 169 3-({[(1R)-6-({4-[(1S)-1-hydroxyethyl]phenyl}(methyl)amino)- B 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid 170 3-({[(1R)-6-{methyl[4-(morpholin-4-yl)phenyl]amino}-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 171 3-({[(1R)-6-[methyl(5-methyl-1,2-oxazol-3-yl)amino]-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 172 3-({[(1R)-6-[(2-methoxyphenyl)(methyl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 173 3-({[(1R)-6-[methyl(pyridin-4-yl)amino]-1,2,3,4- A tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 174 3-({[(1R)-6-{[4-(3,6-dihydro-2H-pyran-4- C yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 175 3-({[(1R)-6-{methyl[4-(oxan-4-yl)phenyl]amino}-1,2,3,4- C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 176 3-({[(4R)-7-[(4-ethenylphenyl)(methyl)amino]-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 177 3-({[(1R)-6-[(4-methoxyphenyl)(methyl)amino]-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 178 3-({[(4R)-7-[(4-methoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1- A benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 179 3-({[(4R)-7-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-3,4- B dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 180 3-({[(1R)-6-{[4-(azetidin-1-yl)phenyl](methyl)amino}-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 181 3-({[(1R)-6-{methyl[4-(trifluoromethoxy)phenyl]amino}-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 182 3-({[(4R)-7-{methyl[4-(trifluoromethoxy)phenyl]amino}-3,4- B C dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 183 3-({[(4R)-7-{[4-(azetidin-1-yl)phenyl](methyl)amino}-3,4-dihydro- B C 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 184 3-({[(1R)-6-{[4-(difluoromethoxy)phenyl](methyl)amino}-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 185 3-({[(1R)-6-[(4-ethoxyphenyl)(methyl)amino]-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 186 3-({[(4R)-7-[(4-ethoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 187 3-({[(4R)-7-{methyl[4-(propan-2-yl)phenyl]amino}-3,4-dihydro- B C 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 188 3-({[(1R)-6-{methyl[4-(1H-pyrazol-1-yl)phenyl]amino}-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 189 3-({[(4R)-7-{methyl[4-(1H-pyrazol-1-yl)phenyl]amino}-3,4- B dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 190 3-({[(4R)-7-{[4-(difluoromethoxy)phenyl](methyl)amino}-3,4- B C dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 191 3-({[(1R)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen- B C 1-yl]methyl}amino)pyridazine-4-carboxylic acid 192 3-({[(4R)-7-{methyl[4-(2,2,2-trifluoroethyl)phenyl]amino}-3,4- B C dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 193 3-({[(1R)-6-{[4-(1H-imidazol-1-yl)phenyl](methyl)amino}-1,2,3,4- B C tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 194 3-({[(4R)-7-{[4-(1H-imidazol-1-yl)phenyl](methyl)amino}-3,4- B C dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 195 3-({[(1R)-6-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino}- B 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid 196 3-({[(4R)-7-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino}- B 3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 197 3-({[(1R)-6-{[4-(2-methoxyethoxy)phenyl](methyl)amino}-1,2,3,4- B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 198 3-({[(4R)-7-(1-phenylethyl)-3,4-dihydro-2H-1-benzopyran-4- B yl]methyl}amino)pyridine-4-carboxylic acid 199 3-({[(4R)-7-{methyl[5-(propan-2-yl)pyridin-2-yl]amino}-3,4- B dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 200 3-({[(1R)-6-{[4-(3-hydroxyazetidin-1-yl)phenyl](methyl)amino}- B 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid 201 3-({[(4R)-7-{[4-(3,6-dihydro-2H-pyran-4- B yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 202 3-({[(4R)-7-{methyl[4-(oxan-4-yl)phenyl]amino}-3,4-dihydro-2H- B C 1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 203 3-({[(4R)-7-(1-phenylcyclopropyl)-3,4-dihydro-2H-1-benzopyran- B 4-yl]methyl}amino)pyridine-4-carboxylic acid 204 3-({[(4R)-7-{methyl[4-(1-methyl-1,2,3,6-tetrahydropyridin-4- A yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid 205 3-({[(4R)-7-{methyl[4-(1-methylpiperidin-4-yl)phenyl]amino}-3,4- A dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 206 3-({[(4R)-7-[(3,4-dimethylphenyl)(methyl)amino]-3,4-dihydro-2H- B 1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 207 3-({[(4R)-7-{[4-(2-hydroxyethyl)phenyl](methyl)amino}-3,4- B dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 208 3-({[(4R)-7-[methyl(4-propylphenyl)amino]-3,4-dihydro-2H-1- C benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 209 3-({[(1R)-6-{[4-(cyclopropylmethoxy)phenyl](methyl)amino}- B C 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid 210 3-({[(4R)-7-{methyl[4-(propan-2-yloxy)phenyl]amino}-3,4- B dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 211 3-({[(4R)-7-{[4-(cyclopropylmethoxy)phenyl](methyl)amino}-3,4- B dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 212 3-({[(4R)-7-[methyl(4-propoxyphenyl)amino]-3,4-dihydro-2H-1- B benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 213 3-({[(4R)-7-[(4-cyclopropoxyphenyl)(methyl)amino]-3,4-dihydro- B 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 214 3-({[(4R)-7-{methyl[4-(2,2,2-trifluoroethoxy)phenyl]amino}-3,4- B dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 215 3-({[(4R)-7-{[4-(cyclopropylmethyl)phenyl](methyl)amino}-3,4- B dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 216 3-({[(4R)-7-[(4-cyclopropanecarbonylphenyl)(methyl)amino]-3,4- B dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid Note: Biochemical assay IC₅₀ data are designated within the following ranges: A: ≦100 nM B: >100 nM to ≦1000 nM C: >1000 nM to ≦10,000 nM D: >10,000 nM

The ability of the following two compounds to inhibit JMJD3 or JMJD2C under the enzymatic assay conditions described herein was determined. 3-({[(4S)-7-phenyl-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid (Example 83 of U.S. Pat. No. 8,952,151) had a JMJD3 IC₅₀ of 0.019 μM and a JMJD2C IC₅₀ of 0.950 μM. 3-({[(4R)-7-phenyl-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid (Example 84 of U.S. Pat. No. 8,952,151) had a JMJD3 IC₅₀ of 2.15 μM and a JMJD2C IC₅₀ of 0.150 μM. The S-enantiomer was >100-fold more potent for JMJD3 than the R-enantiomer. The R-enantiomer was about 6-fold more potent for JMJD2C than the S-enantiomer.

Example 2: In Vitro Cell-Based Assay

The primary cellular assay for JMJD2C inhibition is an assay which measures cellular proliferation via Bromodeoxyuridine (BrdU) incorporation after 168 hours of compound incubation. Cell lines tested include the JMJD2C gene amplified cell line KYSE-150. This is a quantitative ELISA assay measuring DNA incorporation of BrdU during S-phase as a direct readout of cellular proliferation.

Assay Principle: This is a colorimetric immunoassay for the quantification of cell proliferation. Cells treated for 168 hours with test compounds are assayed for their ability to go through S-phase as a measure of their proliferative potential.

Assay Method: The human KYSE-150 (SMAD4 mut, TP53 mut) esophageal carcinoma cell line was seeded at 2,000 cells/well on a 96-well tissue culture treated plate. After an overnight incubation, cells were treated with compound in an 11-point dilution series with final concentrations ranging from 100 μM to 2 nM. Cells were then incubated in the presence of compound for 168 hours. After compound incubation the cells were assayed using a BrdU Cell Proliferation ELISA (Roche). The cells were first incubated with BrdU labeling reagent for 2 hours. After 2 hours, the BrdU incorporated cells were fixed and denatured, probed with an anti-BrdU-Peroxidase antibody for 1.5 hours and washed. Finally, a tetramethylbenzidine peroxidase substrate was added to each well for 15 minutes followed by a H₂SO₄ stop solution. The plate was read at 450 nm, and the raw optical density data was transferred into XLFit (IDBS) for IC₅₀ calculation using the formula:

fit=(D+((Vmax*(x̂n))/((x̂n)+(Km̂n))))

Table 4 provides the cellular IC₅₀ values of various compounds disclosed herein.

TABLE 4 Example Cellular IC₅₀ (μM) 2 A 3 D 4 B 5 B 6 A 7 A 8 A 9 A 10 A 11 A 12 B 13 B 14 D 15 C 16 B 17 B 18 A 19 A 20 A 21 A 22 A 23 A 24 A 25 D 26 C 27 C 28 C 30 B 32 C 34 B 35 C 37 B 38 D 40 A 42 B 43 A 44 B 45 B 46 A 48 C 49 C 51 C 53 B 55 B 56 C 58 A 59 C 61 C 63 D 64 A 65 B 66 A 67 B 69 B 71 B 73 B 73 B 77 A 79 A 80 C 82 D 84 D 86 D 88 D 89 D 91 C 92 C 93 C 94 B 95 D 97 C 99 C 101 A 102 B 103 B 104 B 105 A 106 B 109 B 110 A 111 B 112 C 114 B 115 B 116 B 117 B 119 B 120 B 121 A 122 A 123 A 124 C 125 B 126 B 127 B 131 A 132 A 133 C 134 A 135 A 136 A 139 A 140 A 141 B 142 D 144 A 145 A 146 A 147 B 148 B 150 A 151 A 152 B 153 A 154 A 155 D 156 B 157 A 158 B 159 C 160 A 161 A 163 A 164 A 165 C 166 D 167 A 168 A 169 A 170 A 171 D 172 B 173 D 174 A 175 A 176 A 177 A 178 A 179 A 180 A 183 A 184 A 185 A 186 A 187 A 188 A 189 B 190 A 191 A 192 A 193 B 194 C 196 A 197 A 198 A 199 A 200 B 201 A 202 A 203 B 204 D 205 D 206 A 207 B 208 A 209 A 210 A 211 A 212 A 213 A 214 A Note: Biochemical assay IC₅₀ data are designated within the following ranges: A: ≦0.10 μM B: >0.10 μM to ≦1.0 μM C: >1.0 μM to ≦10 μM D: >10 μM

Example 3: In Vivo Xenograph Study

Time release pellets containing 0.72 mg 17-β Estradiol are subcutaneously implanted into nu/nu mice. MCF-7 cells are grown in RPMI containing 10% FBS at 5% CO₂, 37° C. Cells are spun down and re-suspended in 50% RPMI (serum free) and 50% Matrigel at 1×10⁷ cells/mL. MCF-7 cells are subcutaneously injected (100 μL/animal) on the right flank 2-3 days post pellet implantation and tumor volume (length×width²/2) is monitored bi-weekly. When tumors reach an average volume of ˜200 mm³ animals are randomized and treatment is started. Animals are treated with vehicle or compound daily for 4 weeks. Tumor volume and body weight are monitored bi-weekly throughout the study. At the conclusion of the treatment period, plasma and tumor samples are taken for pharmacokinetic and pharmacodynamic analyses, respectively.

III. Preparation of Pharmaceutical Dosage Forms Example 1: Oral Tablet

A tablet is prepared by mixing 48% by weigh of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, 45% by weight of microcrystalline cellulose, 5% by weight of low-substituted hydroxypropyl cellulose, and 2% by weight of magnesium stearate. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 250-500 mg. 

We claim:
 1. A compound, or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure of Formula (II):

wherein, X is O or CH₂; R⁶ is chosen from optionally substituted heterocyclyl, optionally substituted heterocyclyloxy, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or optionally substituted alkyl, and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—; and each R⁵, R⁷ and R⁸ is independently chosen from hydrogen, halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted C₃-C₇ carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy, optionally substituted C₄-C₁₂ carbocyclylalkyl, optionally substituted C₄-C₁₂ carbocyclylalkoxy, optionally substituted C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl, optionally substituted C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy, optionally substituted C₆-C₁₀ aryl-S—, optionally substituted C₇-C₁₄ aralkoxy, optionally substituted heteroaryl, and optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclyloxy, substituted heterocyclylalkyl, optionally substituted heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or optionally substituted alkyl, and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—; with the provision that at least one of R⁵, R⁷ and R⁸ is hydrogen.
 2. The compound, or pharmaceutically acceptable salt thereof, of claim 1 having the structure of Formula (IIa):

wherein, X is O or CH₂; R⁶ is chosen from optionally substituted heterocyclyl, optionally substituted heterocyclyloxy, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or optionally substituted alkyl, and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—; and each R⁵, R⁷ and R⁸ is independently chosen from hydrogen, halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, optionally substituted C₃-C₇ carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy, optionally substituted C₄-C₁₂ carbocyclylalkyl, optionally substituted C₄-C₁₂ carbocyclylalkoxy, optionally substituted C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl, optionally substituted C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy, optionally substituted C₆-C₁₀ aryl-S—, optionally substituted C₇-C₁₄ aralkoxy, optionally substituted heteroaryl, and optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclyloxy, substituted heterocyclylalkyl, optionally substituted heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or optionally substituted alkyl, and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—; with the provision that at least one of R⁵, R⁷ and R⁸ is hydrogen.
 3. The compound, or pharmaceutically acceptable salt thereof, of claim 2, wherein X is O.
 4. The compound, or pharmaceutically acceptable salt thereof, of claim 2, wherein X is CH₂.
 5. The compound, or pharmaceutically acceptable salt thereof, of claim 2, wherein R⁵ is hydrogen.
 6. The compound, or pharmaceutically acceptable salt thereof, of claim 2, wherein R⁷ is hydrogen.
 7. The compound, or pharmaceutically acceptable salt thereof, of claim 2, wherein R⁸ is hydrogen.
 8. The compound, or pharmaceutically acceptable salt thereof, of claim 2, wherein R⁵, R⁷ and R⁸ are hydrogen.
 9. The compound, or pharmaceutically acceptable salt thereof, of claim 2, wherein R⁶ is optionally substituted heterocyclyl, or optionally substituted heterocyclyloxy.
 10. The compound, or pharmaceutically acceptable salt thereof, of claim 2, wherein R⁶ is optionally substituted C₆-C₁₀ aryl-SO₂—, or optionally substituted heteroaryl-S—.
 11. The compound, or pharmaceutically acceptable salt thereof, of claim 2, wherein R⁶ is —N(R¹)(R²), wherein R¹ is hydrogen; and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.
 12. The compound, or pharmaceutically acceptable salt thereof, of claim 2, wherein R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.
 13. The compound, or pharmaceutically acceptable salt thereof, of claim 8, wherein R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.
 14. The compound, or pharmaceutically acceptable salt thereof, of claim 13, wherein R² is optionally substituted aryl.
 15. The compound, or pharmaceutically acceptable salt thereof, of claim 13, wherein R² is optionally substituted heteroaryl.
 16. The compound, or pharmaceutically acceptable salt thereof, of claim 13, wherein R² is optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—, optionally substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.
 17. The compound, or pharmaceutically acceptable salt thereof, of claim 14, wherein R¹ is an optionally substituted C1-C3 alkyl.
 18. The compound, or pharmaceutically acceptable salt thereof, of claim 14, wherein R¹ is CH₃ group.
 19. The compound, or pharmaceutically acceptable salt thereof, of claim 14, wherein the optionally substituted aryl is substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, halogen, cyano, hydroxy, amino, optionally substituted C1-C5 alkoxy, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkoxy, or optionally substituted cycloalkoxy.
 20. The compound, or pharmaceutically acceptable salt thereof, of claim 14, wherein the optionally substituted aryl is substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, halogen, optionally substituted C1-C5 alkoxy, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkoxy, or optionally substituted cycloalkoxy.
 21. The compound, or pharmaceutically acceptable salt thereof, of claim 14, wherein the optionally substituted aryl is substituted with at least one substituent selected from optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkoxy, or optionally substituted cycloalkoxy.
 22. The compound, or pharmaceutically acceptable salt thereof, of claim 14, wherein the optionally substituted aryl is substituted with at least one substituent selected from optionally substituted C1-C5 alkyl, halogen, or optionally substituted C1-C5 alkoxy.
 23. The compound, or pharmaceutically acceptable salt thereof, of claim 14, wherein the optionally substituted aryl is substituted with at least one optionally substituted C1-C5 alkyl.
 24. The compound, or pharmaceutically acceptable salt thereof, of claim 22, wherein R¹ is a CH₃ group, and X is O.
 25. The compound, or pharmaceutically acceptable salt thereof, of claim 2, having the structure:


26. The compound, or pharmaceutically acceptable salt thereof, of claim 2, having the structure:


27. The compound, or pharmaceutically acceptable salt thereof, of claim 2, having the structure:


28. The compound, or pharmaceutically acceptable salt thereof, of claim 2, having the structure:


29. The compound, or pharmaceutically acceptable salt thereof, of claim 2, having the structure:


30. A pharmaceutical composition comprising a compound of Formula (II) as described in claim 1, or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient.
 31. A method of inhibiting a histone demethylase JMJD3 enzyme comprising contacting the histone demethylase JMJD3 enzyme with a compound of Formula (II) as described in claim
 1. 32. A method of treating cancer in a subject in need thereof, comprising administering to the subject a composition comprising of Formula (II) as described in claim 1, or pharmaceutically acceptable salt thereof. 